U.S. patent application number 12/683352 was filed with the patent office on 2011-02-17 for targeted antimicrobial moieties.
This patent application is currently assigned to C3 JIAN, INC.. Invention is credited to MAXWELL ANDERSON, RANDAL H. ECKERT, JIAN HE, CHRIS KAPLAN, JEE-HYUN SIM, DANIEL K. YARBROUGH.
Application Number | 20110039763 12/683352 |
Document ID | / |
Family ID | 42316784 |
Filed Date | 2011-02-17 |
United States Patent
Application |
20110039763 |
Kind Code |
A1 |
ECKERT; RANDAL H. ; et
al. |
February 17, 2011 |
TARGETED ANTIMICROBIAL MOIETIES
Abstract
This invention provides novel targeted antimicrobial
compositions. In various embodiments chimeric moieties are provided
comprising an antimicrobial peptide attached to a peptide targeting
moiety that binds a bacterial strain or species.
Inventors: |
ECKERT; RANDAL H.; (Redondo
Beach, CA) ; KAPLAN; CHRIS; (Los Angeles, CA)
; HE; JIAN; (Los Angeles, CA) ; YARBROUGH; DANIEL
K.; (Los Angeles, CA) ; ANDERSON; MAXWELL;
(Sequim, WA) ; SIM; JEE-HYUN; (Garden Grove,
CA) |
Correspondence
Address: |
Weaver Austin Villeneuve & Sampson LLP
P.O. BOX 70250
OAKLAND
CA
94612-0250
US
|
Assignee: |
C3 JIAN, INC.
Inglewood
CA
|
Family ID: |
42316784 |
Appl. No.: |
12/683352 |
Filed: |
January 6, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61142830 |
Jan 6, 2009 |
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61151445 |
Feb 10, 2009 |
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61243905 |
Sep 18, 2009 |
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61243930 |
Sep 18, 2009 |
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Current U.S.
Class: |
514/2.4 ; 435/34;
514/1.1; 514/2.3; 514/3.3; 514/3.5; 514/3.7; 514/4.4; 530/300;
530/350 |
Current CPC
Class: |
A61K 9/0063 20130101;
A61P 31/10 20180101; A61K 47/34 20130101; C07K 7/06 20130101; G01N
33/569 20130101; A61K 38/16 20130101; Y02A 50/30 20180101; A61K
41/10 20200101; A61P 31/00 20180101; A01N 37/46 20130101; A61K
47/26 20130101; A61K 38/08 20130101; A61K 8/64 20130101; C07K
14/001 20130101; A61K 47/6911 20170801; A61P 31/04 20180101; A61K
41/0057 20130101; A61K 47/10 20130101; A61K 38/10 20130101; A61K
41/0071 20130101; A61K 47/64 20170801; A61K 9/0019 20130101; A61K
9/06 20130101; C07K 7/08 20130101; A61Q 11/00 20130101 |
Class at
Publication: |
514/2.4 ;
530/300; 530/350; 514/1.1; 514/2.3; 514/3.3; 514/3.5; 435/34;
514/3.7; 514/4.4 |
International
Class: |
A61K 38/00 20060101
A61K038/00; C07K 2/00 20060101 C07K002/00; C07K 14/00 20060101
C07K014/00; A01N 37/18 20060101 A01N037/18; C12Q 1/04 20060101
C12Q001/04; A61P 31/00 20060101 A61P031/00; A01P 1/00 20060101
A01P001/00 |
Claims
1. A chimeric construct, said construct selected from the group
comprising: an effector attached to a peptide targeting moiety
comprising an amino acid sequence found in Table 3 and/or Table 12;
and an antimicrobial peptide comprising an amino acid sequence
found in Table 4 and/or Table 5 attached to a targeting moiety.
2. The chimeric construct of claim 1, wherein said targeting moiety
is a peptide comprising an amino acid sequence of a peptide found
in Table 3 and/or Table 12.
3-5. (canceled)
6. The chimeric construct of claim 1, wherein said effector
comprises a moiety selected from the group consisting of an
antimicrobial peptide, an antibiotic, a ligand, a lipid or
liposome, a agent that physically disrupts the extracellular matrix
within a community of microorganisms, and a polymeric particle.
7. The chimeric construct of claim 1, wherein said effector
comprises an antimicrobial peptide comprising an amino acid
sequence found in Table 4, and/or Table 5, and/or Table 14, and/or
Table 15.
8. (canceled)
9. The chimeric construct of claim 1, wherein said effector
comprises an antimicrobial peptide comprising an amino acid
sequence characterized by a motif selected from the group
consisting of KIF, FIK, KIH, HIK, and KIV.
10. The chimeric construct of claim 1, comprising a targeting
peptide comprising an amino acid sequence found in Table 3 attached
to an antimicrobial peptide comprising an amino acid sequence found
in Table 4 and/or Table 5.
11. The chimeric construct of claim 1, comprising an antimicrobial
peptide comprising an amino acid sequence found in Table 4 attached
to a targeting moiety comprising an amino acid sequence found in
Table 3 and/or Table 10, and/or Table 12.
12. The chimeric construct of claim 1, comprising a targeting
peptide comprising an amino acid sequence found in Table 3 attached
to an antimicrobial peptide comprising an amino acid sequence found
in Table 4.
13. The chimeric construct of claim 1, wherein said targeting
moiety is chemically conjugated to said effector.
14. The chimeric construct of claim 13, wherein said targeting
moiety is chemically conjugated to said effector via a linker.
15. The chimeric construct of claim 13, wherein said targeting
moiety is chemically conjugated to said effector via a linker
comprising a polyethylene glycol (PEG).
16. The chimeric construct of claim 13, wherein said targeting
moiety is chemically conjugated to said effector via a non-peptide
linker found in Table 16.
17. The chimeric construct of claim 1, wherein said targeting
moiety is linked directly to said effector.
18. The chimeric construct of claim 1, wherein said targeting
moiety is linked to said effector via a peptide linkage.
19. The chimeric construct of claim 18, wherein said effector
comprises an antimicrobial peptide and said construct is a fusion
protein.
20. The chimeric construct of claim 18, wherein said targeting
moiety is attached to said effector by a peptide linker comprising
or consisting of an amino acid sequence found in Table 16.
21. The chimeric construct of claim 1, wherein said construct bears
one or more protecting groups.
22-24. (canceled)
25. The chimeric construct of claim 1, wherein said construct is
functionalized with a polymer to increase serum halflife.
26. (canceled)
27. A pharmaceutical composition comprising a chimeric construct of
claim 1 in a pharmaceutically acceptable carrier.
28. (canceled)
29. The composition of claim 27, wherein said composition is
formulated for administration by a modality selected from the group
consisting of intraperitoneal administration, topical
administration, oral administration, inhalation administration,
transdermal administration, subdermal depot administration, and
rectal administration.
30. An antimicrobial composition effective to kill or to inhibit
the growth and/or of a microorganism and/or the formation and/or
maintenance of a biofilm, said composition comprising one or more
isolated antimicrobial peptides, the amino acid sequences of said
peptides comprising one or more sequences selected from the amino
acid sequences listed in Table 4 and/or Table 5.
31. The composition according to claim 30, wherein said composition
is effective to kill or inhibit the growth and/or proliferation of
a yeast or fungus, and said composition comprises one or more
peptides, the amino acid sequences of said peptides comprising one
or more sequences selected from the group of amino acid sequences
listed in Table 4 and/or Table 5 identified as effective to
effective to kill or inhibit the growth and/or proliferation of a
yeast or fungus.
32. The composition according to claim 31, wherein said composition
is effective to kill or inhibit the growth and/or proliferation of
Aspergillus niger and said composition comprises one or more
peptides, the amino acid sequences of said peptides comprising one
or more sequences selected from the group of amino acid sequences
listed in Table 4 and/or Table 5 identified as effective to
effective to kill or inhibit the growth and/or proliferation of
Aspergillus niger.
33. The composition according to claim 31, wherein said composition
is effective to kill or inhibit the growth and/or proliferation of
C. albicans and said composition comprises one or more peptides,
the amino acid sequences of said peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of C. albicans.
34. The composition according to claim 31, wherein said composition
is effective to kill or inhibit the growth and/or proliferation of
T. rubrum and said composition comprises one or more peptides, the
amino acid sequences of said peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of T. rubrum.
35. The composition according to claim 30, wherein said composition
is effective to kill or inhibit the growth and/or proliferation of
a bacterium, and said composition comprises one or more peptides,
the amino acid sequences of said peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of a bacterium.
36-55. (canceled)
56. The composition of claim 30, wherein said peptides comprise all
"L" amino acids.
57. The composition of claim 30, wherein said peptides comprise all
"D" amino acids.
58. The composition of claim 30, wherein said peptides comprise a
mixture of "L" and "D" amino acids.
59. The composition of claim 30, wherein said peptides are 0
peptides.
60. The composition of claim 30, wherein said peptides comprise one
or more protecting groups.
61-65. (canceled)
66. A method of killing and/or inhibiting the growth and/or
proliferation of a microorganism, said method comprising contacting
said microorganism with a chimeric construct of claim 1, or a
composition of claim 30.
67. The method of claim 66, wherein said microorganism is a yeast
or fungus and said chimeric construct or composition is a chimeric
construct of claim 1 comprising an effector identified as killing a
yeast or fungus, or a binding moiety identified as binding a yeast
or fungus.
68-80. (canceled)
81. A method of detecting a bacterium and/or a bacterial film, said
method comprising: contacting said bacterium or bacterial film with
a composition comprising a detectable label attached to a targeting
peptide comprising one or more amino acid sequences found Table 3
and/or Table 12; and detecting said detectable label wherein the
quantity and/or location of said detectable label is an indicator
of the presence of said bacterium and/or bacterial film.
82. The method of claim 81, wherein said targeting peptide
comprises or consists of an amino acid sequence of a peptide found
in Table 3.
83. The method of claim 81, wherein said detectable label is a
label selected from the group consisting of a radioactive label, a
radio-opaque label, a fluorescent dye, a fluorescent protein, an
enzymatic label, a colorimetric label, and a quantum dot.
84. A composition comprising a photosensitizing agent attached to a
targeting peptide comprising an amino acid sequence of a peptide
found in Table 3 and/or Table 12.
85. The composition of claim 84, wherein said targeting peptide
comprises or consists of an amino acid sequence of a peptide found
in Table 3.
86. The composition of claim 84, wherein said photosensitizing
agent is an agent selected from the group consisting of a
porphyrinic macrocycle, a porphyrin, a chlorine, a crown ether, an
acridine, an azine, a phthalocyanine, a cyanine, a cucumin, a
psoralen, and a perylenequinonoid.
87. The composition of claim 84, wherein said photosensitizing
agent is an agent shown in any of FIGS. 1-12.
88-90. (canceled)
91. A method of inhibiting the growth or proliferation of a
microorganism or a biofilm, said method comprising contacting said
microorganism or biofilm with a composition of claim 84.
92. The method of claim 91, further comprising exposing said
microorganism or biofilm to a light source.
93. The method of claim 91, wherein said microorganism is a
microorganism selected from the group consisting of a bacterium, a
yeast, a fungus, a protozoan, and a virus.
94. The method of claim 91, wherein said biofilm comprises a
bacterial film.
95. The method of claim 91, wherein said biofilm is a biofilm on an
implanted or implantable medical device.
96. The method of claim 91, wherein said microorganism or biofilm
is an organism or biofilm in an oral cavity.
97. A formulation comprising: a targeting peptide, an antimicrobial
peptide, and/or a STAMP; and a salt at a concentration comparable
to that found in phosphate buffered saline (PBS) ranging from about
0.5.times.PBS to about 2.5.times.PBS.
98. The formulation of claim 97, wherein said formulation comprises
a targeting peptide found in Tables 3 or 10.
99-103. (canceled)
104. The formulation of claim 97, wherein said formulation
comprises the amino acid sequence of the C16G2 STAMP
(TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY (SEQ ID NO:23252).
105-112. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of and priority to U.S. Ser.
No. 61/142,830, filed Jan. 6, 2009, U.S. Ser. No. 61/151,445, filed
Feb. 10, 2009, U.S. Ser. No. 61/243,905, filed Sep. 18, 2009, and
U.S. Ser. No. 61/243,930, filed Sep. 18, 2009, all of which are
incorporated herein by reference in their entirety for all
purposes.
STATEMENT OF GOVERNMENTAL SUPPORT
[0002] [Not Applicable]
FIELD OF THE INVENTION
[0003] The present invention relates to novel targeting peptides,
novel antimicrobial peptides, chimeric moieties comprising novel
targeting and/or novel antimicrobial peptides and uses thereof.
BACKGROUND OF THE INVENTION
[0004] Antibiotic research at the industrial level was originally
focused on the identification of refined variants of already
existing drugs. This resulted example, in the development of
antibiotics such as newer penicillins, cephalosporins, macrolides,
and fluoroquinolones.
[0005] However, resistance to old and newer antibiotics among
bacterial pathogens is evolving rapidly, as exemplified by extended
beta-lactamase (ESBL) and quinolone resistant gram-negatives,
multi-resistant gonococci, methicillin resistant Staphylococcus
aureus (MRSA), vancomycin resistant enterococci (VRE), penicillin
non-susceptible pneumococci (PNSP) and macrolide resistant
pneumococci and streptococci (see, e.g., Panlilo et al. (1992)
Infect Control Hosp Epidemio., 13: 582-586; Morris et al. (1995)
Ann Intern Me., d 123: 250-259, and the like). An overuse, or
improper use, of antibiotics is believed to be of great importance
for triggering and spread of drug resistant bacteria. Microbes
have, in many cases, adapted and are resistant to antibiotics due
to constant exposure and improper use of the drugs.
[0006] Drug resistant pathogens represent a major economic burden
for health-care systems. For example, postoperative and other
nosocomial infections will prolong the need for hospital care and
increase antibiotic drug expenses. It is estimated that the annual
cost of treating drug resistant infections in the United States is
approximately $5 billion.
SUMMARY OF THE INVENTION
[0007] In certain embodiments, novel targeting moieties (e.g.,
peptides) that specifically/preferentially bind to microorganisms
(e.g., certain bacteria, yeasts, fungi, molds, viruses, algae,
protozoa, and the like) are provided. The targeting moieties can be
attached to effectors (e.g., detectable labels, drugs,
antimicrobial peptides, etc.) to form chimeric constructs for
specifically/preferentially delivering the effector to and/or into
the target organism. In certain embodiments novel antimicrobial
peptides that can be used to inhibit (e.g., kill and/or inhibit
growth and/or proliferation) of certain microorganisms (e.g.,
certain bacteria, yeasts, fungi, molds, viruses, algae, protozoa,
and the like) are provided.
[0008] Accordingly, in certain embodiments, a chimeric construct
(chimeric moiety) is provided comprising: an effector attached to a
peptide targeting moiety comprising an amino acid sequence found in
Table 3 and/or Table 12; and/or an antimicrobial peptide comprising
an amino acid sequence found in Table 4 and/or Table 5 attached to
a targeting moiety. In certain embodiments the targeting moiety is
a peptide comprising an amino acid sequence of a peptide found one
or more of Table 3 and Table 12. In certain embodiments the
targeting moiety is a peptide comprising two or more amino acid
sequences of a peptide found one or more of Table 3 and Table 12.
In certain embodiments the targeting moiety is a peptide whose
amino acid sequence consists of the amino acid sequence of a
peptide found in Table 3.
[0009] In various embodiments the effector comprises a moiety
selected from the group consisting of an antimicrobial peptide, an
antibiotic, a ligand, a lipid or liposome, a agent that physically
disrupts the extracellular matrix within a community of
microorganisms, and a polymeric particle. In certain embodiments
the effector comprises an antimicrobial peptide comprising an amino
acid sequence found in one or more of Tables 4, 5, 14, and Table
15. In certain embodiments the effector comprises an antimicrobial
peptide comprising an amino acid sequence found in one or more of
Tables 4, and 5. In certain embodiments the effector comprises an
antimicrobial peptide comprising an amino acid sequence
characterized by a motif selected from the group consisting of KIF,
FIK, KIH, HIK, and KIV (e.g., as identified in Table 7). In certain
embodiments the construct comprises a targeting peptide comprising
an amino acid sequence found in Table 3 attached to an
antimicrobial peptide comprising an amino acid sequence found in
Table 4 and/or Table 5. In certain embodiments the construct
comprises an antimicrobial peptide comprising an amino acid
sequence found in Table 4 attached to a targeting moiety comprising
an amino acid sequence found in Table 3 and/or Table 10, and/or
Table 12. In certain embodiments the construct comprises a
targeting peptide comprising an amino acid sequence found in Table
3 attached to an antimicrobial peptide comprising an amino acid
sequence found in Table 4.
[0010] In various embodiments the targeting moiety is chemically
conjugated to the effector (directly or via a linker). In certain
embodiments the linker comprises a polyethylene glycol (PEG). In
certain embodiments the targeting moiety is chemically conjugated
to the effector via a non-peptide linker found in Table 16. In
certain embodiments the targeting moiety is linked to the effector
via a peptide linkage. In certain embodiments the effector
comprises an antimicrobial peptide and the construct is a fusion
protein. In certain embodiments the targeting moiety is attached to
the effector by a peptide linker comprising or consisting of an
amino acid sequence found in Table 16. In certain embodiments any
of the constructs and/or peptides described herein bears one or
more protecting groups. In certain embodiments the one or more
protecting groups are independently selected from the group
consisting of acetyl, amide, 3 to 20 carbon alkyl groups, fmoc,
tboc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group,
9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group,
benzyloxycarbonyl, xanthyl (Xan), trityl (Trt), 4-methyltrityl
(Mtt), 4-methoxytrityl (Mmt),
4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr),
mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), tosyl
(Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc),
4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO),
benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys),
1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde),
2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl
(2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), benzyloxymethyl (Bom),
t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Bum),
t-butoxy (tBuO), t-Butyl (tBu), and trifluoroacetyl (TFA). In
certain embodiments the peptide and/or construct comprises a
protecting group at a carboxyl and/or amino terminus. In certain
embodiments the carboxyl terminus is amidated and/or the amino
terminus is acetylated. In various embodiments the chimeric
construct and/or peptide is functionalized with a polymer (e.g.,
comprises polyethylene glycol, cellulose, modified cellulose,
dextrin, etc.) to increase serum halflife.
[0011] In certain embodiments pharmaceutical compositions are
provided. In various embodiments the pharmaceutical compositions
comprise a chimeric construct as described herein (e.g., a chimeric
construct according to any of claims 1-26) and/or an antimicrobial
peptide as described herein, in a pharmaceutically acceptable
carrier. In certain embodiments the composition is formulated as a
unit dosage formulation. In certain embodiments the composition is
formulated for administration by a modality selected from the group
consisting of intraperitoneal administration, topical
administration, oral administration, inhalation administration,
transdermal administration, subdermal depot administration,
systemic IV application, ocular administration, and rectal
administration.
[0012] In certain embodiments isolated antimicrobial peptides are
provided. In various embodiments the peptides comprise one or more
sequences selected from the amino acid sequences listed in Table 4
and/or Table 5 (and/or the retro, inverso, retroinverso, or beta
forms). In various embodiments the antimicrobial peptide bears one
or more protecting groups e.g., as described herein.
[0013] In certain embodiments a composition effective to kill or to
inhibit the growth and/or of a microorganism and/or the formation
and/or maintenance of a biofilm is provided. The composition
typically comprises one or more isolated antimicrobial peptides,
the amino acid sequences of the peptides comprising one or more
sequences selected from the amino acid sequences listed in Table 4
and/or Table 5 (and/or their retro, inverso, or retroinverso
forms). In certain embodiments the composition is effective to kill
or inhibit the growth and/or proliferation of a yeast or fungus,
and the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified (e.g., in those tables) as effective to
effective to kill or inhibit the growth and/or proliferation of a
yeast or fungus. In certain embodiments the composition is
effective to kill or inhibit the growth and/or proliferation of
Aspergillus niger and the composition comprises one or more
peptides, the amino acid sequences of the peptides comprising one
or more sequences selected from the group of amino acid sequences
listed in Table 4 and/or Table 5 identified as effective to
effective to kill or inhibit the growth and/or proliferation of
Aspergillus niger. In certain embodiments the composition is
effective to kill or inhibit the growth and/or proliferation of C.
albicans and the composition comprises one or more peptides, the
amino acid sequences of the peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of C. albicans. In
certain embodiments the composition is effective to kill or inhibit
the growth and/or proliferation of T. rubrum and the composition
comprises one or more peptides, the amino acid sequences of the
peptides comprising one or more sequences selected from the group
of amino acid sequences listed in Table 4 and/or Table 5 identified
as effective to effective to kill or inhibit the growth and/or
proliferation of T. rubrum. In certain embodiments the composition
is effective to kill or inhibit the growth and/or proliferation of
a bacterium, and the composition comprises one or more peptides,
the amino acid sequences of the peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of a bacterium. In
certain embodiments the composition is effective to kill or inhibit
the growth and/or proliferation of a gram positive bacterium, and
the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of a gram positive bacterium. In
certain embodiments the composition is effective to kill or inhibit
the growth and/or proliferation of A. naeslundii, and the
composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of A. naeslundii. In certain
embodiments the composition is effective to kill or inhibit the
growth and/or proliferation of B. subtilis, and the composition
comprises one or more peptides, the amino acid sequences of the
peptides comprising one or more sequences selected from the group
of amino acid sequences listed in Table 4 and/or Table 5 identified
as effective to effective to kill or inhibit the growth and/or
proliferation of B. subtilis. In certain embodiments the
composition is effective to kill or inhibit the growth and/or
proliferation of C. difficile, and the composition comprises one or
more peptides, the amino acid sequences of the peptides comprising
one or more sequences selected from the group of amino acid
sequences listed in Table 4 and/or Table 5 identified as effective
to effective to kill or inhibit the growth and/or proliferation of
C. difficile. In certain embodiments the composition is effective
to kill or inhibit the growth and/or proliferation of C. jeikeium,
and the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of C. jeikeium. In certain embodiments
the composition is effective to kill or inhibit the growth and/or
proliferation of E. faecalis, and the composition comprises one or
more peptides, the amino acid sequences of the peptides comprising
one or more sequences selected from the group of amino acid
sequences listed in Table 4 and/or Table 5 identified as effective
to effective to kill or inhibit the growth and/or proliferation of
E. faecalis. In certain embodiments the composition is effective to
kill or inhibit the growth and/or proliferation of M. luteus, and
the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of M. luteus. In certain embodiments
the composition is effective to kill or inhibit the growth and/or
proliferation of MRSA, and the composition comprises one or more
peptides, the amino acid sequences of the peptides comprising one
or more sequences selected from the group of amino acid sequences
listed in Table 4 and/or Table 5 identified as effective to
effective to kill or inhibit the growth and/or proliferation of
MRSA. In certain embodiments composition is effective to kill or
inhibit the growth and/or proliferation of S. epidermidis, and the
composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of S. epidermidis. In certain
embodiments the composition is effective to kill or inhibit the
growth and/or proliferation of S. mutans, and the composition
comprises one or more peptides, the amino acid sequences of the
peptides comprising one or more sequences selected from the group
of amino acid sequences listed in Table 4 and/or Table 5 identified
as effective to effective to kill or inhibit the growth and/or
proliferation of S. mutans. In certain embodiments the composition
is effective to kill or inhibit the growth and/or proliferation of
S. pneumoniae, and the composition comprises one or more peptides,
the amino acid sequences of the peptides comprising one or more
sequences selected from the group of amino acid sequences listed in
Table 4 and/or Table 5 identified as effective to effective to kill
or inhibit the growth and/or proliferation of S. pneumoniae. In
certain embodiments the composition is effective to kill or inhibit
the growth and/or proliferation of a gram negative bacterium, and
the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of a gram negative bacterium. In
certain embodiments the composition is effective to kill or inhibit
the growth and/or proliferation of A. baumannii, and the
composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of A. baumannii. In certain embodiments
the composition is effective to kill or inhibit the growth and/or
proliferation of C. jejuni, and the composition comprises one or
more peptides, the amino acid sequences of the peptides comprising
one or more sequences selected from the group of amino acid
sequences listed in Table 4 and/or Table 5 identified as effective
to effective to kill or inhibit the growth and/or proliferation of
C. jejuni. In certain embodiments the composition is effective to
kill or inhibit the growth and/or proliferation of E. coli, and the
composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of E. coli. In certain embodiments the
composition is effective to kill or inhibit the growth and/or
proliferation of F. nucleatum, and the composition comprises one or
more peptides, the amino acid sequences of the peptides comprising
one or more sequences selected from the group of amino acid
sequences listed in Table 4 and/or Table 5 identified as effective
to effective to kill or inhibit the growth and/or proliferation of
F. nucleatum. In certain embodiments the composition is effective
to kill or inhibit the growth and/or proliferation of E. coli, and
the composition comprises one or more peptides, the amino acid
sequences of the peptides comprising one or more sequences selected
from the group of amino acid sequences listed in Table 4 and/or
Table 5 identified as effective to effective to kill or inhibit the
growth and/or proliferation of M. xanthus. In certain embodiments
the composition is effective to kill or inhibit the growth and/or
proliferation of P. aeruginosa, and the composition comprises one
or more peptides, the amino acid sequences of the peptides
comprising one or more sequences selected from the group of amino
acid sequences listed in Table 4 and/or Table 5 identified as
effective to effective to kill or inhibit the growth and/or
proliferation of P. aeruginosa. In certain embodiments the
composition is effective to kill or inhibit the growth and/or
proliferation of P. gingivalis, and the composition comprises one
or more peptides, the amino acid sequences of the peptides
comprising one or more sequences selected from the group of amino
acid sequences listed in Table 4 and/or Table 5 identified as
effective to effective to kill or inhibit the growth and/or
proliferation of P. gingivalis. In certain embodiments the
composition is effective to kill or inhibit the growth and/or
proliferation of P. mirabilis, and the composition comprises one or
more peptides, the amino acid sequences of the peptides comprising
one or more sequences selected from the group of amino acid
sequences listed in Table 4 and/or Table 5 identified as effective
to effective to kill or inhibit the growth and/or proliferation of
P. mirabilis.
[0014] In various embodiments one or more of the peptides
comprising the composition comprise all "L" amino acids or all "D"
amino acids, or a mixture of "L" and "D" amino acids. In various
embodiments one or more of the peptides comprising the composition
are .beta. peptides. In various embodiments one or more of the
peptides comprising the composition comprise one or more protecting
groups (e.g. protected carboxyl and/or amino termini). In various
embodiments one or more of the peptides comprising the composition
comprise an amide on the carboxyl terminus and/or an acetyl on the
amino terminus. In various embodiments the peptides comprising the
composition are in a pharmaceutically acceptable carrier. In
certain embodiments the carrier is suitable for administration via
a route selected from the group consisting of topical
administration, aerosol administration, administration via
inhalation, oral administration, and/or rectal administration.
[0015] In various embodiments methods are provided for killing
and/or inhibiting the growth and/or proliferation of a
microorganism and or for disrupting and/or inhibiting the growth
and/or maintenance of a biofilm, the method comprising contacting
the microorganism (or a biofilm comprising the microorganism) with
a chimeric construct as described herein (e.g., see description
above, and/or a chimeric construct according to any one of claims
1-29), or with an antimicrobial peptide as described herein, and/or
with a composition as described herein (e.g., a composition
according to any one of claims 30-65). In certain embodiments the
microorganism is a yeast or fungus and the chimeric construct or
composition is a chimeric construct comprising an effector
identified as killing a yeast or fungus, or a composition
comprising an antimicrobial peptide described herein as killing a
yeast or fungus. In certain embodiments the microorganism is a
bacterium (e.g., gram negative and/or gram positive bacterium) and
the chimeric construct or composition is a chimeric construct
comprising an effector identified as killing a bacterium (e.g.,
gram negative and/or gram positive bacterium), or a composition
comprising an antimicrobial peptide described herein as killing a
gram negative and/or gram positive bacterium. In certain
embodiments the effector is an antimicrobial peptide. In certain
embodiments the microorganism is S. mutans, and the chimeric
construct or composition is applied to the oral cavity of an animal
or human, e.g., to reduces the incidence or severity of dental
caries and/or periodontal disease). In certain embodiments the
chimeric construct or composition preferentially targets
Corynebacterium spp. and the chimeric construct or composition is
applied to the skin surface of an animal or human (e.g., to reduce
body odor).
[0016] Methods are also provided for disinfecting a surface. The
methods typically involve contacting the surface with one or more
chimeric constructs described herein (e.g. a construct according to
any one of claims 1-29), or a composition as described herein
(e.g., a composition according to any one of claims 30-65). In
certain embodiments, the surface comprises a surface of a
prosthesis or medical implant. In certain embodiments the surface
comprises a surface of a medical device. In certain embodiments the
surface comprises a surface of a plant or foodstuff. In certain
embodiments the chimeric construct and/or the antimicrobial
peptide(s) are combined with a second disinfectant selected from
the group consisting of other antimicrobial agent is a disinfectant
selected from the group consisting of acetic acid, phosphoric acid,
citric acid, lactic, formic, propionic acid, hydrochloric acid,
sulfuric acid, nitric acid, sodium hydroxide, potassium hydroxide,
sodium carbonate, ammonium hydroxide, ethyl alcohol, isopropyl
alcohol, phenol, formaldehyde, glutaraldehyde, hypochlorites,
chlorine dioxide, sodium dichloroisocyanurate, chloramine-T,
iodine, povidone-iodine, chlorhexidine, hydrogen peroxide,
peracetic acid, and benzalkonium chloride.
[0017] In various embodiments the use of a chimeric construct
described herein and/or an antimicrobial composition as described
herein (e.g., a chimeric construct according to any one of claims
1-29, or a composition according to any one of claims 30-65) in the
manufacture of a medicament for killing and/or inhibiting the
growth and/or proliferation of a microorganism and/or inhibiting
the growth and/or maintenance of a biofilm comprising the
microorganism is provided. In certain embodiments the microorganism
is a yeast or fungus and the chimeric construct or composition is a
chimeric construct comprising an effector identified as killing a
yeast or fungus, or a composition comprising an antimicrobial
peptide described herein as killing a yeast or fungus. In certain
embodiments the microorganism is a bacterium (e.g., gram negative
and/or gram positive bacterium) and the chimeric construct or
composition is a chimeric construct comprising an effector
identified as killing a bacterium (e.g., gram negative and/or gram
positive bacterium), or a composition comprising an antimicrobial
peptide described herein as killing a gram negative and/or gram
positive bacterium. In certain embodiments the effector is an
antimicrobial peptide.
[0018] In various embodiments methods are also provided for of
detecting a bacterium and/or a bacterial film (e.g., a biofilm
comprising the bacteria). The methods typically involve contacting
the bacterium or bacterial film with a composition comprising a
detectable label attached to a targeting peptide comprising one or
more amino acid sequences found Table 3 and/or Table 12; and
detecting the detectable label where the quantity and/or location
of the detectable label is an indicator of the presence of the
bacterium and/or bacterial film. In certain embodiments the
targeting peptide comprises or consists of an amino acid sequence
of a peptide found in Table 3 (and/or the retro, inverso,
retroinverso form of the sequence). In certain embodiments the
detectable label is a label selected from the group consisting of a
radioactive label, a radio-opaque label, a fluorescent dye, a
fluorescent protein, an enzymatic label, a colorimetric label, and
a quantum dot.
[0019] Certain compositions are also provided comprising a
photosensitizing or photoactivatable agent attached to a targeting
peptide (e.g., a peptide comprising an amino acid sequence of a
peptide found in Table 3 and/or Table 12). In certain embodiments
the targeting peptide comprises or consists of an amino acid
sequence of a peptide found in Table 3. In certain embodiments the
photosensitizing agent is an agent selected from the group
consisting of a porphyrinic macrocycle, a porphyrin, a chlorine, a
crown ether, an acridine, an azine, a phthalocyanine, a cyanine, a
psoralen, a cucumin, and a perylenequinonoid. In certain
embodiments the photosensitizing agent comprises one or more agents
agent shown in any of FIGS. 1-12. In certain embodiments the
photosensitizing agent is attached to the targeting peptide by a
non-peptide linker (e.g., a polyethylene glycol (PEG)). In certain
embodiments the photosensitizing agent is attached to the targeting
peptide by a non-peptide linker found in Table 16.
[0020] In various embodiments methods are provided for killing
and/or for inhibiting the growth and/or proliferation of a
microorganism or a biofilm comprising a microorganism, where the
methods involve contacting the microorganism or biofilm with a
composition comprising a photosensitizing or photoactivatable agent
attached to a targeting peptide (e.g., a peptide comprising an
amino acid sequence of a peptide found in Table 3 and/or Table 12).
In certain embodiments the targeting peptide comprises or consists
of an amino acid sequence of a peptide found in Table 3. In certain
embodiments the photosensitizing agent is an agent selected from
the group consisting of a porphyrinic macrocycle, a porphyrin, a
chlorine, a crown ether, an acridine, an azine, a phthalocyanine, a
cyanine, a psoralen, a cucumin, and a perylenequinonoid. In certain
embodiments the photosensitizing agent comprises one or more agents
agent shown in any of FIGS. 1-12. In certain embodiments the
photosensitizing agent is attached to the targeting peptide by a
non-peptide linker (e.g., a polyethylene glycol (PEG)). In certain
embodiments the photosensitizing agent is attached to the targeting
peptide by a non-peptide linker found in Table 16. In certain
embodiments the method further comprises exposing the microorganism
or biofilm to a light source. In certain embodiments the
microorganism is a microorganism selected from the group consisting
of a bacterium (e.g., a gram positive and/or a gram negative
bacterium), a yeast, a fungus, a protozoan, and a virus. In certain
embodiments the biofilm comprises a bacterial film. In certain
embodiments the biofilm is a biofilm on an implanted or implantable
medical device. In certain embodiments the microorganism or biofilm
is an organism or biofilm in an oral cavity.
[0021] In various embodiments certain formulations are provided.
Typical formulations include, but are not limited to a targeting
peptide, an antimicrobial peptide, and/or a STAMP; and a salt at a
concentration comparable to that found in phosphate buffered saline
(PBS) ranging from about 0.5.times.PBS to about 2.5.times.PBS. In
certain embodiments the formulation comprises a targeting peptide
found in Tables 3 or 10. In certain embodiments the formulation
comprises an anti-S. mutans peptide targeting peptide (e.g., as
identified in Tables 3 or 12). In certain embodiments the anti-S.
mutans targeting peptide has the amino acid sequence
TFFRLFNRSFTQALGK (SEQ ID NO:1). In certain embodiments the anti-S.
mutans targeting peptide is attached to an antimicrobial peptide.
In certain embodiments the antimicrobial peptide is a peptide found
in Tables 4, 5, or 14. In certain embodiments the antimicrobial
peptide has the amino acid sequence KNLRIIRKGIHIIKKY (SEQ ID
NO:3080). In certain embodiments the formulation comprises the
amino acid sequence of the C16G2 STAMP
(TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY, (SEQ ID NO:2). In various
embodiments the targeting peptide, antimicrobial peptide, and/or a
STAMP bears one or more protecting groups. In certain embodiments
the protecting group(s) are independently selected from the group
consisting of acetyl, amide, 3 to 20 carbon alkyl groups, Fmoc,
Tboc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group,
9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group,
benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl
(Mtt), 4-methoxytrityl (Mmt),
4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr),
Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl
(Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc),
4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO),
Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys),
1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde),
2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl
(2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Bom),
t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO), t-butoxymethyl (Bum),
t-butoxy (tBuO), t-Butyl (tBu), and Trifluoroacetyl (TFA). In
certain embodiments the targeting peptide, antimicrobial peptide,
and/or a STAMP is amidated at the carboxyl terminus and/or bears an
acetyl group at the amino terminus. In certain embodiments the pH
of the formulation ranges from about pH 5.0 to about pH 8.5. In
certain embodiments the pH is about pH 7.4. In various embodiments
the salt is at a concentration comparable to that found in
1.times.PBS. In certain embodiments the formulation comprises PBS.
In certain embodiments the formulation of further comprising
ethanol, and/or glycerin, and/or polyethylene glycol, and/or
fluoride.
DEFINITIONS
[0022] The term "peptide" as used herein refers to a polymer of
amino acid residues typically ranging in length from 2 to about 50
or about 60 residues. In certain embodiments the peptide ranges in
length from about 2, 3, 4, 5, 7, 9, 10, or 11 residues to about 60,
50, 45, 40, 45, 30, 25, 20, or 15 residues. In certain embodiments
the peptide ranges in length from about 8, 9, 10, 11, or 12
residues to about 15, 20 or 25 residues. In certain embodiments the
amino acid residues comprising the peptide are "L-form" amino acid
residues, however, it is recognized that in various embodiments,
"D" amino acids can be incorporated into the peptide. Peptides also
include amino acid polymers in which one or more amino acid
residues is an artificial chemical analogue of a corresponding
naturally occurring amino acid, as well as to naturally occurring
amino acid polymers. In addition, the term applies to amino acids
joined by a peptide linkage or by other, "modified linkages" (e.g.,
where the peptide bond is replaced by an .alpha.-ester, a
.beta.-ester, a thioamide, phosphoamide, carbonate, hydroxylate,
and the like (see, e.g., Spatola, (1983) Chem. Biochem. Amino Acids
and Proteins 7: 267-357), where the amide is replaced with a
saturated amine (see, e.g., Skiles et al., U.S. Pat. No. 4,496,542,
which is incorporated herein by reference, and Kaltenbronn et al.,
(1990) Pp. 969-970 in Proc. 11th American Peptide Symposium, ESCOM
Science Publishers, The Netherlands, and the like)).
[0023] The term "residue" as used herein refers to natural,
synthetic, or modified amino acids. Various amino acid analogues
include, but are not limited to 2-aminoadipic acid, 3-aminoadipic
acid, beta-alanine (beta-aminopropionic acid), 2-aminobutyric acid,
4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid,
2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric
acid, 2-aminopimelic acid, 2,4 diaminobutyric acid, desmosine,
2,2'-diaminopimelic acid, 2,3-diaminopropionic acid,
n-ethylglycine, n-ethylasparagine, hydroxylysine,
allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline,
isodesmosine, allo-isoleucine, n-methylglycine, sarcosine,
n-methylisoleucine, 6-n-methyllysine, n-methylvaline, norvaline,
norleucine, ornithine, and the like. These modified amino acids are
illustrative and not intended to be limiting.
[0024] ".beta.-peptides" comprise of ".beta. amino acids", which
have their amino group bonded to the .beta. carbon rather than the
.alpha.-carbon as in the 20 standard biological amino acids. The
only commonly naturally occurring .beta. amino acid is
.beta.-alanine
[0025] Peptoids, or N-substituted glycines, are a specific subclass
of peptidomimetics. They are closely related to their natural
peptide counterparts, but differ chemically in that their side
chains are appended to nitrogen atoms along the molecule's
backbone, rather than to the .alpha.-carbons (as they are in
natural amino acids).
[0026] The terms "conventional" and "natural" as applied to
peptides herein refer to peptides, constructed only from the
naturally-occurring amino acids: Ala, Cys, Asp, Glu, Glu, Phe, Gly,
His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp,
and Tyr. A compound of the invention "corresponds" to a natural
peptide if it elicits a biological activity (e.g., antimicrobial
activity) related to the biological activity and/or specificity of
the naturally occurring peptide. The elicited activity may be the
same as, greater than or less than that of the natural peptide. In
general, such a peptoid will have an essentially corresponding
monomer sequence, where a natural amino acid is replaced by an
N-substituted glycine derivative, if the N-substituted glycine
derivative resembles the original amino acid in hydrophilicity,
hydrophobicity, polarity, etc. The following are illustrative, but
non-limiting N-substituted glycine replacements:
N-(1-methylprop-1-yl)glycine substituted for isoleucine (Ile),
N-(prop-2-yl)glycine for valine (Val), N-benzylglycine for
phenylanlaine (Phe), N-(2-hydroxyethyl)glycine for serine (Ser),
and the like. In certain embodiments substitutions need not be
"exact". Thus for example, in certain embodiments
N-(2-hydroxyethyl)glycine may substitute for Ser, Thr, Cys, and/or
Met; N-(2-methylprop-1-yl)glycine may substitute for Val, Leu,
and/or Ile. In certain embodiments N-(2-hydroxyethyl)glycine can be
used to substitute for Thr and Ser, despite the structural
differences: the side chain in N-(2-hydroxyethyl)glycine is one
methylene group longer than that of Ser, and differs from Thr in
the site of hydroxy-substitution. In general, one may use an
N-hydroxyalkyl-substituted glycine to substitute for any polar
amino acid, an N-benzyl- or N-aralkyl-substituted glycine to
replace any aromatic amino acid (e.g., Phe, Trp, etc.), an
N-alkyl-substituted glycine such as N-butylglycine to replace any
nonpolar amino acid (e.g., Leu, Val, Ile, etc.), and an
N-(aminoalkyl)glycine derivative to replace any basic polar amino
acid (e.g., Lys and Arg).
[0027] Where an amino acid sequence is provided herein, L-, D-, or
beta amino acid versions of the sequence are also contemplated as
well as retro, inversion, and retro-inversion isoforms. In
addition, conservative substitutions (e.g., in the binding peptide,
and/or antimicrobial peptide, and/or linker peptide) are
contemplated. Non-protein backbones, such as PEG, alkane, ethylene
bridged, ester backbones, and other backbones are also
contemplated. Also fragments ranging in length from about 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
or 25 amino acids up to the full length minus one amino acid of the
peptide are contemplated where the fragment retains at least 50%,
preferably at least 60% 70% or 80%, more preferably at least 90%,
95%, 98%, 99%, or at least 100% of the activity (e.g., binding
specificity and/or avidity, antimicrobial activity, etc.) of the
full length peptide are contemplated.
[0028] A "compound antimicrobial peptide" or "compound AMP" refers
to a construct comprising two or more AMPs joined together. The
AMPs can be joined directly or through a linker. They can be
chemically conjugated or, where joined directly together or through
a peptide linker can comprise a fusion protein.
[0029] In certain embodiments, conservative substitutions of the
amino acids comprising any of the sequences described herein are
contemplated. In various embodiments one, two, three, four, or five
different residues are substituted. The term "conservative
substitution" is used to reflect amino acid substitutions that do
not substantially alter the activity (e.g., antimicrobial activity
and/or specificity) of the molecule. Typically conservative amino
acid substitutions involve substitution one amino acid for another
amino acid with similar chemical properties (e.g. charge or
hydrophobicity). Certain conservative substitutions include "analog
substitutions" where a standard amino acid is replaced by a
non-standard (e.g., rare, synthetic, etc) amino acid differing
minimally from the parental residue. Amino acid analogs are
considered to be derived synthetically from the standard amino
acids without sufficient change to the structure of the parent, are
isomers, or are metabolite precursors. Examples of such "analog
substitutions" include, but are not limited to, 1) Lys-Orn, 2)
Leu-Norleucine, 3) Lys-Lys[TFA], 4) Phe-Phe[Gly], and 5)
.delta.-amino butylglycine-.xi.-amino hexylglycine, where Phe[gly]
refers to phenylglycine (a Phe derivative with a H rather than
CH.sub.3 component in the R group), and Lys[TFA] refers to a Lys
where a negatively charged ion (e.g., TFA) is attached to the amine
R group. Other conservative substitutions include "functional
substitutions" where the general chemistries of the two residues
are similar, and can be sufficient to mimic or partially recover
the function of the native peptide. Strong functional substitutions
include, but are not limited to 1) Gly/Ala, 2) Arg/Lys, 3)
Ser/Tyr/Thr, 4) Leu/Ile/Val, 5) Asp/Glu, 6) Gln/Asn, and 7)
Phe/Trp/Tyr, while other functional substitutions include, but are
not limited to 8) Gly/Ala/Pro, 9) Tyr/His, 10) Arg/Lys/His, 11)
Ser/Thr/Cys, 12) Leu/Ile/Val/Met, and 13) Met/Lys (special case
under hydrophobic conditions). Various "broad conservative
substations" include substitutions where amino acids replace other
amino acids from the same biochemical or biophysical grouping. This
is similarity at a basic level and stems from efforts to classify
the original 20 natural amino acids. Such substitutions include 1)
nonpolar side chains: Gly/Ala/Val/Leu/Ile/Met/Pro/Phe/Trp, and/or
2) uncharged polar side chains Ser/Thr/Asn/Gln/Tyr/Cys. In certain
embodiments broad-level substitutions can also occur as paired
substitutions. For example, Any hydrophilic neutral pair [Ser, Thr,
Gln, Asn, Tyr, Cys]+[Ser, Thr, Gln, Asn, Tyr, Cys] can may be
replaced by a charge-neutral charged pair [Arg, Lys, His]+[Asp,
Glu]. The following six groups each contain amino acids that, in
certain embodiments, are typical conservative substitutions for one
another: 1) Alanine (A), Serine (S), Threonine (T); 2) Aspartic
acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4)
Arginine (R), Lysine (K), Histidine (H); 5) Isoleucine (I), Leucine
(L), Methionine (M), Valine (V); and 6) Phenylalanine (F), Tyrosine
(Y), Tryptophan (W). Where amino acid sequences are disclosed
herein, amino acid sequences comprising, one or more of the
above-identified conservative substitutions are also
contemplated.
[0030] In certain embodiments, targeting peptides, antimicrobial
peptides, and/or STAMPs compromising at least 80%, preferably at
least 85% or 90%, and more preferably at least 95% or 98% sequence
identity with any of the sequences described herein are also
contemplated. The terms "identical" or percent "identity," refer to
two or more sequences that are the same or have a specified
percentage of amino acid residues that are the same, when compared
and aligned for maximum correspondence, as measured using one of
the following sequence comparison algorithms or by visual
inspection. With respect to the peptides of this invention sequence
identity is determined over the full length of the peptide. For
sequence comparison, typically one sequence acts as a reference
sequence, to which test sequences are compared. When using a
sequence comparison algorithm, test and reference sequences are
input into a computer, subsequence coordinates are designated, if
necessary, and sequence algorithm program parameters are
designated. The sequence comparison algorithm then calculates the
percent sequence identity for the test sequence(s) relative to the
reference sequence, based on the designated program parameters.
Optimal alignment of sequences for comparison can be conducted,
e.g., by the local homology algorithm of Smith & Waterman
(1981) Adv. Appl. Math. 2: 482, by the homology alignment algorithm
of Needleman & Wunsch (1970) J. Mol. Biol. 48: 443, by the
search for similarity method of Pearson & Lipman (1988) Proc.
Natl. Acad. Sci., USA, 85: 2444, by computerized implementations of
these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin
Genetics Software Package, Genetics Computer Group, 575 Science
Dr., Madison, Wis.), or by visual inspection.
[0031] The term "specificity" when used with respect to the
antimicrobial activity of a peptide indicates that the peptide
preferentially inhibits growth and/or proliferation and/or kills a
particular microbial species as compared to other related and/or
unrelated microbes. In certain embodiments the preferential
inhibition or killing is at least 10% greater (e.g., LD.sub.50 is
10% lower), preferably at least 20%, 30%, 40%, or 50%, more
preferably at least 2-fold, at least 5-fold, or at least 10-fold
greater for the target species.
[0032] "Treating" or "treatment" of a condition as used herein may
refer to preventing the condition, slowing the onset or rate of
development of the condition, reducing the risk of developing the
condition, preventing or delaying the development of symptoms
associated with the condition, reducing or ending symptoms
associated with the condition, generating a complete or partial
regression of the condition, or some combination thereof.
[0033] The term "consisting essentially of" when used with respect
to an antimicrobial peptide (AMP) or AMP motif as described herein,
indicates that the peptide or peptides encompassed by the library
or variants, analogues, or derivatives thereof possess
substantially the same or greater antimicrobial activity and/or
specificity as the referenced peptide. In certain embodiments
substantially the same or greater antimicrobial activity indicates
at least 80%, preferably at least 90%, and more preferably at least
95% of the anti microbial activity of the referenced peptide(s)
against a particular bacterial species (e.g., S. mutans).
[0034] The term "porphyrinic macrocycle" refers to a porphyrin or
porphyrin derivative. Such derivatives include porphyrins with
extra rings ortho-fused, or orthoperifused, to the porphyrin
nucleus, porphyrins having a replacement of one or more carbon
atoms of the porphyrin ring by an atom of another element (skeletal
replacement), derivatives having a replacement of a nitrogen atom
of the porphyrin ring by an atom of another element (skeletal
replacement of nitrogen), derivatives having substituents other
than hydrogen located at the peripheral (meso-, .beta.-) or core
atoms of the porphyrin, derivatives with saturation of one or more
bonds of the porphyrin (hydroporphyrins, e.g., chlorins,
bacteriochlorins, isobacteriochlorins, decahydroporphyrins,
corphins, pyrrocorphins, etc.), derivatives obtained by
coordination of one or more metals to one or more porphyrin atoms
(metalloporphyrins), derivatives having one or more atoms,
including pyrrolic and pyrromethenyl units, inserted in the
porphyrin ring (expanded porphyrins), derivatives having one or
more groups removed from the porphyrin ring (contracted porphyrins,
e.g., corrin, corrole) and combinations of the foregoing
derivatives (e.g. phthalocyanines, porphyrazines,
naphthalocyanines, subphthalocyanines, and porphyrin isomers).
Certain porphyrinic macrocycles comprise at least one 5-membered
ring.
[0035] As used herein, an "antibody" refers to a protein consisting
of one or more polypeptides substantially encoded by immunoglobulin
genes or fragments of immunoglobulin genes. The recognized
immunoglobulin genes include the kappa, lambda, alpha, gamma,
delta, epsilon and mu constant region genes, as well as myriad
immunoglobulin variable region genes. Light chains are classified
as either kappa or lambda. Heavy chains are classified as gamma,
mu, alpha, delta, or epsilon, which in turn define the
immunoglobulin classes, IgG, IgM, IgA, IgD and IgE,
respectively.
[0036] A typical immunoglobulin (antibody) structural unit is known
to comprise a tetramer. Each tetramer is composed of two identical
pairs of polypeptide chains, each pair having one "light" (about 25
kD) and one "heavy" chain (about 50-70 kD). The N-terminus of each
chain defines a variable region of about 100 to 110 or more amino
acids primarily responsible for antigen recognition. The terms
variable light chain (V.sub.L) and variable heavy chain (V.sub.H)
refer to these light and heavy chains respectively.
[0037] Antibodies exist as intact immunoglobulins or as a number of
well characterized fragments produced by digestion with various
peptidases. Thus, for example, pepsin digests an antibody below the
disulfide linkages in the hinge region to produce F(ab)'.sub.2, a
dimer of Fab which itself is a light chain joined to
V.sub.H-C.sub.H1 by a disulfide bond. The F(ab)'.sub.2 may be
reduced under mild conditions to break the disulfide linkage in the
hinge region thereby converting the (Fab').sub.2 dimer into an Fab'
monomer. The Fab' monomer is essentially an Fab with part of the
hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven
Press, N.Y. (1993), for a more detailed description of other
antibody fragments). While various antibody fragments are defined
in terms of the digestion of an intact antibody, one of skill will
appreciate that such Fab' fragments may be synthesized de novo
either chemically or by utilizing recombinant DNA methodology.
Thus, the term antibody, as used herein also includes antibody
fragments either produced by the modification of whole antibodies
or synthesized de novo using recombinant DNA methodologies,
including, but are not limited to, Fab'.sub.2, IgG, IgM, IgA, scFv,
dAb, nanobodies, unibodies, and diabodies.
[0038] In certain embodiments antibodies and fragments of the
present invention can be bispecific. Bispecific antibodies or
fragments can be of several configurations. For example, bispecific
antibodies may resemble single antibodies (or antibody fragments)
but have two different antigen binding sites (variable regions). In
various embodiments bispecific antibodies can be produced by
chemical techniques (Kranz et al. (198 1) Proc. Natl. Acad. Sci.,
USA, 78: 5807), by "polydoma" techniques (see, e.g., U.S. Pat. No.
4,474,893), or by recombinant DNA techniques. In certain
embodiments bispecific antibodies of the present invention can have
binding specificities for at least two different epitopes, at least
one of which is an epitope of a microbial organism. The microbial
binding antibodies and fragments can also be heteroantibodies.
Heteroantibodies are two or more antibodies, or antibody binding
fragments (e.g., Fab) linked together, each antibody or fragment
having a different specificity.
[0039] The term "STAMP" refers to Specifically Targeted
Anti-Microbial Peptides. In various embodiments, a STAMP comprises
one or more peptide targeting moieties attached to one or more
antimicrobial moieties (e.g., antimicrobial peptides (AMPs)). An
MH-STAMP is a STAMP bearing two or more targeting domains (i.e., a
multi-headed STAMP).
[0040] The terms "isolated" "purified" or "biologically pure" refer
to material which is substantially or essentially free from
components that normally accompany it as found in its native state.
In the case of a peptide, an isolated (naturally occurring) peptide
is typically substantially free of components with which it is
associated in the cell, tissue, or organism. The term isolated also
indicates that the peptide is not present in a phage display, yeast
display, or other peptide library.
[0041] In various embodiments the amino acid abbreviations shown in
Table 1 are used herein.
TABLE-US-00001 TABLE1 Amino acid abbreviations. Abbreviation Name 3
Letter 1 Letter Alanine Ala A .beta.Alanine
(NH.sub.2--CH.sub.2--CH.sub.2--COOH) .beta.Ala Arginine Arg R
Asparagine Asn N Aspartic Acid Asp D Cysteine Cys C Glutamic Acid
Glu E Glutamine Gln Q Glycine Gly G Histidine His H Homoserine Hse
-- Isoleucine Ile I Leucine Leu L Lysine Lys K Methionine Met M
Methionine sulfoxide Met (O) -- Methionine methylsulfonium Met
(S-Me) -- Norleucine Nle -- Phenylalanine Phe F Proline Pro P
Serine Ser S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine
Val V episilon-aminocaproic acid Ahx J
(NH.sup.2--(CH.sub.2).sub.5--COOH) 4-aminobutanoic acid gAbu
(NH.sub.2--(CH.sub.2).sub.3--COOH) tetrahydroisoquinoline-3- O
carboxylic acid Lys(N(epsilon)-trifluoroacetyl) K[TFA]
.alpha.-aminoisobutyric acid Aib B
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 shows some illustrative porphyrins (compounds 92-99)
suitable for use as targeting moieties and/or antimicrobial
effectors.
[0043] FIG. 2 shows some illustrative porphyrins (compounds
100-118) suitable for use as targeting moieties and/or
antimicrobial effectors.
[0044] FIG. 3 shows some illustrative porphyrins (in particular
phthalocyanines) (compounds 119-128) suitable for use as targeting
moieties and/or antimicrobial effectors.
[0045] FIG. 4 illustrates the structures of two phthalocyanines,
Monoastral Fast Blue B and Monoastral Fast Blue G suitable for use
as targeting moieties and/or antimicrobial effectors.
[0046] FIG. 5 illustrates certain azine photosensitizers suitable
for use as targeting moieties and/or antimicrobial effectors in the
compositions and methods described herein.
[0047] FIG. 6 shows illustrative cyanine suitable for use as
targeting moieties and/or antimicrobial effectors in the
compositions and methods described herein.
[0048] FIG. 7 shows illustrative psoralen (angelicin)
photosensitizers suitable for use as targeting moieties and/or
antimicrobial effectors in the compositions and methods described
herein.
[0049] FIG. 8 shows illustrative hypericin and the
perylenequinonoid pigments suitable for use as targeting moieties
and/or antimicrobial effectors in the compositions and methods
described herein.
[0050] FIG. 9 shows illustrative acridines suitable for use as
targeting moieties and/or antimicrobial effectors in the
compositions and methods described herein.
[0051] FIG. 10 illustrates the structure of the acridine Rose
Bengal.
[0052] FIG. 11 illustrates various crown ethers suitable for use as
targeting moieties and/or antimicrobial effectors in the
compositions and methods described herein.
[0053] FIG. 12 illustrates the structure of cumin.
[0054] FIG. 13 illustrates an example of a targeted light-activated
porphyrin we have constructed: C16-P18 comprising a porphyrin
coupled to a C16 (SEQ ID NO:3) targeting sequence.
[0055] FIG. 14 schematically shows some illustrative configurations
for chimeric constructs described herein. A: Shows a single
targeting moiety T1 attached to a single effector E1 by a
linker/spacer L. B: Shows multiple targeting moieties T1, T2, T3
attached directly to each other and attached by a linker L to a
single effector E1. In various embodiments T1, T2, and T3, can be
domains in a fusion protein. C: Shows multiple targeting moieties
T1, T2, T3 attached to each other by linkers L and attached by a
linker L to a single effector E1. In various embodiments T1, T2,
and T3, can be domains in a fusion protein. D: Shows a single
targeting moiety T1 attached by a linker L to multiple effectors
E1, E2, and E3 joined directly to each other. E: Shows a single
targeting moiety T1 attached by a linker L to multiple effectors
E1, E2, and E3 joined to each other by linkers L. F: Shows multiple
targeting moieties joined directly to each other and by a linker L
to multiple effectors joined to each other by linkers L. G: Shows
multiple targeting moieties joined to each other by linkers L and
by a linker L to multiple effectors joined to each other by linkers
L. In various embodiments T1, T2, and T3, and/or E1, E2, and E3 can
be domains in a fusion protein. H: Illustrates a branched
configuration where multiple targeting moieties are linked to a
single effector. I: Illustrates a dual branched configuration where
multiple targeting moieties are linked to multiple effectors. J:
Illustrates a branched configuration where multiple targeting
moieties are linked to multiple effectors where the effectors are
joined to each other in a linear configuration.
[0056] FIG. 15 illustrates various MH-STAMPs used in Example 1. The
design, sequence, and observed mass (m/z) for M8(KH)-20 (SEQ ID
NOs:4, 5, and 6), BL(KH)-20 (SEQ ID 7, 8, and 9), and M8(BL)-20
(SEQ ID 10, 11, and 12).
[0057] FIGS. 16A and 16B show HPLC and MS spectra of M8(KH)-20. The
quality of the completed MH-STAMP was analyzed by HPLC (FIG. 16A)
and MALDI mass spectroscopy (FIG. 16B). At UV absorbance 215 nm
(260 and 280 nm are also plotted), a single major product was
detected by HPLC (* retention volume 11.04 mL). After fraction
collection, the correct mass (m/z) for single-charged M8(KH)-20,
4884.91 (marked by *), was observed for this peak. Y-axis: 16A, mAU
miliabsorbance units; 16B, percent intensity.
[0058] FIG. 17A-17E show growth inhibitory activity of MH-STAMPs.
Monocultures of S. mutans (FIG. 17A); P. aeruginosa (FIG. 17B); S.
epidermidis (FIG. 17C); S. aureus (FIG. 17D); or E. coli (FIG.
17E); were treated with peptides (as indicated in the figure) for
10 min. Agent was then removed and fresh media returned. Culture
recovery was measured over time (OD600). Plots represent the
average of at least 3 independent experiments with standard
deviations.
[0059] FIG. 18 illustrates the selective activity of dual-targeted
and single-targeted MH-STAMPs in mixed culture. A mixture of P.
aeruginosa (Pa), S. mutans (Sm), E. coli (Ec), and S. epidermidis
(Se) planktonic cells were mixed with MH-STAMPs (as indicated in
the figure) and treated 24 h. After incubation, cfu/mL of remaining
constituent species were quantitated after plating to selective
media. * indicates under 200 surviving cfu/mL recovered.
[0060] FIGS. 19A and 19B illustrate Rose Bengal (FIG. 19A) and
synthesis scheme for C16-RB, halides and side-chains omitted for
clarity (FIG. 19B).
[0061] FIG. 20 shows LC/MS profile C16-RB. Purity and molecular
mass of C16-RB was confirmed by LC/MS. A single product was
observed at 11.92 min with mass species at 1040.8 and 1560.25
daltons. Expected C16-RB mas: m/z=3118, m.sup.2+/z=1559,
m.sup.3+/Z=1039.
[0062] FIG. 21 illustrates activity of RB and C16-RB against
single-species S. mutans biofilms. * indicates fewer than 100
cfu/mL recovered
[0063] FIG. 22 shows S. mutans-specific C16-RB activity. C16-RB,
and not RB alone, preferentially eliminated S. mutans, and not
other oral streptococci, after blue light illumination.
DETAILED DESCRIPTION
[0064] In various embodiments, novel "targeting" peptides are
identified that specifically or preferentially bind particular
microorganisms (e.g., bacteria, yeasts, fungi, etc.). These
peptides can be used alone to bind/capture and thereby identify
and/or isolate particular target microorganisms, or they can be
attached to one or more effectors (e.g., drugs, labels, etc.) and
used as targeting moieties thereby providing a chimeric moiety that
preferentially or specifically delivers the effector to a target
microorganism, a population of target microorganisms, a microbial
film, a biofilm, and the like.
[0065] In various embodiments novel peptides having antimicrobial
activity against certain bacteria, fungi, yeasts, and/or viruses
and/or having activity that inhibits the growth or maintenance of
biofilms comprising such microorganisms are provided. The AMPs can
be used to inhibit the growth and/or proliferation of a microbial
species and/or the growth and/formation and/or maintenance of a
biofilm comprising the microbial species.
[0066] In certain embodiments, the targeting moieties can be
attached to antimicrobial peptides to form Specifically Targeted
Anti-Microbial Peptides (STAMPs). In certain embodiments attachment
of one or more targeting moieties/peptides to one or more
antimicrobial peptides can narrow the spectrum of activity of the
AMP(s) to provide efficacy against one or a few target
microorganisms without substantially disrupting the remaining
microbial ecology and thereby provide increased efficacy with fewer
side effects.
[0067] In certain embodiments STAMPs or effector peptides can be
delivered against pathogenic bacteria by being cloned and expressed
in probiotic organisms for therapeutic delivery in vivo.
Recombinant expression (and overexpression) and export of
antimicrobial peptides and other peptides are well documented in
bacteria, including species that are also utilized as
probiotics.
[0068] In various embodiments the targeting peptides, antimicrobial
peptides, and/or STAMPs can be formulated individually, in
combination with each other, in combination with other
antimicrobial peptides, and/or in combination with various
antibacterial agents to provide antimicrobial reagents and/or
pharmaceuticals.
[0069] Accordingly, in certain embodiments this invention provides
peptides having antimicrobial activity, compositions comprising the
peptides, methods of using the peptides (or compositions thereof)
to inhibit the growth of or kill a wide variety of microbial
targets and methods of using the peptides (or compositions thereof)
to treat or prevent microbial infections and diseases related
thereto in both plants and animals.
[0070] The various peptides (targeting peptides, AMPs, STAMPs,
etc.) described herein exhibit antimicrobial activity, being
biostatic or biocidal against a certain microbial targets,
including but not limited to, Gram-negative bacteria such as
Acinetobacter baumannii, Escherichia coli, Fusobacterium nucleatum,
Pseudomonas aeruginosa, Porphyromonas gingivalis; Gram-positive
bacteria such as Actinomyces naeslundii, Bacillus subtilis,
Clostridium difficile, Enterococcus faecalis, Staphylococcus aureus
(and MRSA), S. epidermidis, Streptococcus mutans, Streptococcus
pneumoniae; and yeast or fungi such as Aspergillus niger, Candida
albicans, Malassezia furfur, and Trichophyton rubrum (see, e.g.,
Table 2). Significantly, various peptides described herein are
biostatic or biocidal against clinically relevant pathogens
exhibiting multi-drug resistance such as, for example,
methicillin-resistant Staphylococcus aureus ("MRSA").
Table 2. Illustrative Target Microorganisms and Associated
Pathology.
TABLE-US-00002 [0071] TABLE 2 Illustrative target microorganisms
and associated pathology. Acinetobacter baumannii Pathogenic
gram-negative bacillus that is naturally sensitive (A. baumannii)
to relatively few antibiotics. Actinomyces naeslundii Gram positive
rod shaped bacteria that occupy the oral (A. naeslundii) cavity and
are implicated in periodontal disease and root caries. Aspergillus
niger A fungal infection that often causes a black mould to appear
(A. niger) on some fruit and vegetables but may also infect humans
through inhalation of fungal spores. Bacteroides fragilis Gram
positive bacilli that are opportunistic human (B. fragilis)
pathogens, causing infections of the peritoneal cavity,
gastrointestinal surgery, and appendicitis via abscess formation,
inhibiting phagocytosis. Resistant to a wide variety of antibiotics
-- .beta.-lactams, aminoglycosides, and recently many species have
acquired resistance to erythromycin and tetracycline. Bacillus
subtilis Gram-positive, catalase-positive bacterium. (B. subtilis)
Candida albicans Causal agent of opportunistic oral and genital
fungal (C. albicans) infections in humans. Clostridium difficile A
gram-positive, anaerobic, spore-forming bacillus that is (C.
difficile) responsible for the development of antibiotic-associated
diarrhea and colitis. Corynebacterium jeikeium Gram positive,
opportunistic pathogen primarily of (C. jeikeium) immunocompromised
(neutropenic) patients. Highly resistant to antibiotics
Campylobacter jejuni Gram negative cause of human
gastroenteritis/food (C. jejuni) poisoning. Escherichia coli Gram
negative rod-shaped bacterium commonly found in the (E. coli) lower
intestine of warm-blooded organisms. Certain strains cause serious
food poisoning in humans. Enterococcus faecalis Gram-positive
commensal bacterium (E. faecalis) Fusobacterium nucleatum Gram
negative schizomycetes bacterium often seen in (F. nucleatum)
necrotic tissue and implicated, but not conclusively, with other
organisms in the causation and perpetuation of periodontal disease.
Lactobacillus acidophilus Gram-positive commensal bacterium. (L.
acidophilus) Legionella pneumophila Gram negative bacterium that is
the causative agent of (L. pneumophila) legionellosis or
Legionnaires' disease. (Micrococcus luteus) Gram positive,
spherical, saprotrophic bacterium found in M. luteus soil, dust,
water and air, and as part of the normal flora of the mammalian
skin. The bacterium also colonizes the human mouth, mucosae,
oropharynx and upper respiratory tract. Considered an emerging
nosocomial pathogen in immunocompromised patients. Mycobacterium
smegmatis Gram-variable (acid-fast) soil-dwelling organism utilized
as (M. smegmatis) a proxy for Mycobacterium tuberculosis during
research and development. Malassezia furfur Yeast - cutaneous
pathogen. (M. furfur) Methicillin-resistant Any strain of
Staphylococcus aureus bacteria (gram positive) Staphylococcus
aureus that is resistant to a one or more members of a large group
of (MRSA) antibiotics called the beta-lactams. Responsible for skin
and systemic infections. Myxococcus xanthus Gram negative cells
that form biofilms and display primitive (M. xanthus) social
motility and fruiting body organization. Pseudomonas aeruginosa
Gram-negative rod. Frequent opportunistic pathogen and P.
aeruginosa infects burn wounds. Causes ear infections in children.
Infects the lungs of cystic fibrosis patients. Porphyromonas
gingivalis Non-motile, gram-negative, rod-shaped, anaerobic (P.
gingivalis) pathogenic bacterium (periodontal disease)
Progeussmirabilis Gram-negative, facultatively anaerobic bacterium.
Causes (P. mirabilis) 90% of all `Proteus` infections in humans. S.
epidermidis Gram-positive, coagulase-negative cocci. Nosocomial (S.
epidermidis) pathogen associated with infection (biofilm) of
implanted medical device. Streptococcus mutans Gram-positive,
facultatively anaerobic bacterium commonly (S. mutans) found in the
human oral cavity and is a significant contributor to tooth decay
Streptococcus pneumoniae Gram-positive, alpha-hemolytic, bile
soluble aerotolerant (S. pneumoniae) anaerobe. Causal agent for
streptococcal pneumonia. Treponema denticola Gram-negative oral
spirochete associated with the incidence (T. denticola) and
severity of human periodontal disease. Trichophyton rubrum Most
common cause of athlete's foot, jock itch and (T. rubrum)
ringworm.
[0072] The various agents described herein (targeting peptides,
compound targeting peptides, antimicrobial peptides (AMPs) and/or
compound AMPs, STAMPs and/or other chimeric moieties). or
compositions thereof, are useful as biocidal or biostatic or
fungicidal or fungistatic agents and/or virucidal agents in a wide
variety of applications. For example, the agents can be used to
disinfect or preserve a variety of materials including medical
instruments, foodstuffs, medicaments, cosmetics and other
nutrient-containing materials. Various peptides described herein
are particularly useful as bacteriostatic or bactericidal agents
against multi-drug-resistant pathogens such as MRSA in a variety of
clinical settings.
[0073] The agents described herein, or compositions thereof, are
also useful for the prophylaxis or treatment of microbial
infections and diseases related thereto in both plants and animals.
Such diseases include, but are not limited to, Gram-negative and
Gram-positive bacterial infections, endocarditis, pneumonia and
other respiratory infections, urinary tract infections, systemic
candidiasis, oral mucositis, fungal infections, biofilm formation
or maintenance (e.g., on medical implants), and the like.
[0074] In various embodiments, the agents described herein can be
formulated individually, in combination with each other, in
combination with other antimicrobial peptides, and/or in
combination with various antibiotic (e.g., antibacterial) agents in
"home healthcare" formulations. Such formulations include, but are
not limited to toothpaste, mouthwash, tooth whitening strips or
solutions, contact lens storage, wetting, or cleaning solutions,
dental floss, toothpicks, toothbrush bristles, oral sprays, oral
lozenges, nasal sprays, aerosolizers for oral and/or nasal
application, wound dressings (e.g., bandages), and the like.
[0075] Such applications are illustrative and not limiting. Using
the teachings provided herein other uses of the AMPs and
compositions described herein will be recognized by one of
I. Targeting Peptides.
[0076] A) Uses of Targeting Peptides.
[0077] The novel microorganism-binding peptides (targeting
peptides) described herein can be used to preferentially or
specifically deliver an effector to a microorganism (e.g., a
bacterium, a fungus, a protozoan, an algae, etc.), to a bacterial
film, to a biofilm, and the like. The targeting peptides described
herein can be used to bind to and thereby label particular targets,
and/or as capture reagents to bind target microorganisms and
thereby provide an indicator of the presence and/or quantity of the
target microorganism(s). In certain embodiments the targeting
peptide can be attached to an effector such as an epitope tag
and/or a detectable label and thereby facilitate the identification
of the presence and/or location, and/or quantity of the target
(e.g., target organism). Thus targeting moieties are thus readily
adapted for use in in vivo diagnostics, and/or ex vivo assays.
Moreover, because of small size and good stability, microorganism
binding peptides are well suited for microassay systems (e.g.,
microfluidic assays (Lab on a Chip), microarray assays, and the
like).
[0078] In certain embodiments the microorganism binding peptides
(targeting peptides) can be attached to an effector that has
antimicrobial activity (e.g., an antimicrobial peptide, an
antibacterial and/or antifungal, a vehicle that contains an
antibacterial or antifungal, etc. In various embodiments these
chimeric moieties can be used in vivo, or ex vivo to preferentially
inhibit or kill the target organism(s).
[0079] In certain embodiments the targeting peptides can be
recombinantly expressed as part of a yeast or phage tail fiber or
coat protein to enhance binding of the yeast or phage to a specific
bacterial Gram-designation, genus, species, or strain. Phage with
expressed peptides will then display altered infection selectivity
towards a designed target bacteria for use in phage therapy.
Cloning the DNA encoding a peptide of interest into the major or
minor coat proteins of a bacteriophage, for example in Proteins I
through VIII of phages SAP-2, M13, or T7, will result in a targeted
phage expressing 1-200 copies of the targeting peptide on the phage
surface.
[0080] In certain embodiments the targeting peptides can be used in
various pre-targeting protocols. In pre-targeting protocols, a
chimeric molecule is utilized comprising a primary targeting
species (e.g. a microorganism-binding peptide) that specifically
binds the desired target (e.g. a bacterium) and an effector that
provides a binding site that is available for binding by a
subsequently administered second targeting species. Once sufficient
accretion of the primary targeting species (the chimeric molecule)
is achieved, a second targeting species comprising (i) a diagnostic
or therapeutic agent and (ii) a second targeting moiety, that
recognizes the available binding site of the primary targeting
species, is administered.
[0081] An illustrative example of a pre-targeting protocol is the
biotin-avidin system for administering a cytotoxic radionuclide to
a tumor. In a typical procedure, a monoclonal antibody targeted
against a tumor-associated antigen is conjugated to avidin and
administered to a patient who has a tumor recognized by the
antibody. Then the therapeutic agent, e.g., a chelated radionuclide
covalently bound to biotin, is administered. The radionuclide, via
its attached biotin is taken up by the antibody-avidin conjugate
pretargeted at the tumor. Examples of pre-targeting biotin/avidin
protocols are described, for example, in Goodwin et al., U.S. Pat.
No. 4,863,713; Goodwin et al. (1988) J. Nucl. Med. 29: 226;
Hnatowich et al. (1987) J. Nucl. Med. 28: 1294; Oehr et al. (1988)
J. Nucl. Med. 29: 728; Klibanov et al. (1988) J. Nucl. Med. 29:
1951; Sinitsyn et al. (1989) J. Nucl. Med. 30: 66; Kalofonos et al.
(1990) J. Nucl. Med. 31: 1791; Schechter et al. (1991) Int. J.
Cancer 48:167; Paganelli et al. (1991) Cancer Res. 51: 5960;
Paganelli et al. (1991) Nucl. Med. Commun. 12: 211; Stickney et al.
(1991) Cancer Res. 51: 6650; and Yuan et al. (1991) Cancer Res.
51:3119.
[0082] It will be recognized that the tumor-specific antibody used
for cancer treatments can be replaced with a microorganism binding
peptide of the present invention and similar pre-targeting
strategies can be used to direct labels, antibiotics, and the like
to the target organism(s).
[0083] Three-step pre-targeting protocols in which a clearing agent
is administered after the first targeting composition has localized
at the target site also have been described. The clearing agent
binds and removes circulating primary conjugate which is not bound
at the target site, and prevents circulating primary targeting
species (antibody-avidin or conjugate, for example) from
interfering with the targeting of active agent species
(biotin-active agent conjugate) at the target site by competing for
the binding sites on the active agent-conjugate. When
antibody-avidin is used as the primary targeting moiety, excess
circulating conjugate can be cleared by injecting a biotinylated
polymer such as biotinylated human serum albumin. This type of
agent forms a high molecular weight species with the circulating
avidin-antibody conjugate which is quickly recognized by the
hepatobiliary system and deposited primarily in the liver.
[0084] Examples of these protocols are disclosed, e.g., in PCT
Application No. WO 93/25240; Paganelli et al. (1991) Nucl. Med.
Comm., 12: 211-234; Oehr et al. (1988) J. Nucl. Med., 29: 728-729;
Kalofonos et al. (1990) J. Nucl. Med., 31: 1791-1796; Goodwin et
al. (1988) J. Nucl. Med., 29: 226-234; and the like).
[0085] These applications of microorganism binding peptides of this
invention are intended to be illustrative and not limiting. Using
the teaching provided herein, other uses will be recognized by one
of skill in the art.
[0086] B) Illustrative Novel Targeting Peptides.
[0087] In certain embodiments, the targeting moiety comprises one
or more targeting peptides that bind particular bacteria, fungi,
and/or yeasts, and/or algae, and/or viruses and/or that bind
particular groups of bacteria, and/or groups of fungi, and/or
groups of yeasts, and/or groups of algae.
[0088] In certain embodiments the targeting peptides include
peptides comprising or consisting of one or more of the amino acid
sequences shown in Table 3 (SEQ ID NOs:13-1566). In various
embodiments the peptides include peptides comprising or consisting
of the retro, inverso, retro-inverso, and/or beta form of one or
more of the amino acid sequences shown in Table 3. Also
contemplated are circular permutations of these sequences as well
as peptides comprising or consisting of the retro, inverso,
retro-inverso, and/or beta form of such circular permutations.
[0089] It will also be recognized, that in certain embodiments, any
peptide or compound AMP described herein can be circularized.
[0090] In various embodiments the peptides can optionally bear one
or more protecting groups, e.g., and the amino and/or carboxyl
termini, and/or on side chains.
[0091] Also contemplated are peptides comprising one, two, three
four, or five conservative substitutions of these amino acid
sequences.
Table 3. Illustrative List of Novel Targeting Peptides.
TABLE-US-00003 [0092] TABLE 3 Illustrative list of novel targeting
peptides. SEQ ID ID Target(s) Targeting Peptide Sequence NO 1T-3 S.
mutans VLGIAGGLDAYGELVGGN 13 S. gordonii 1T-4 S. mutans LDAYGELVGGN
14 S. gordonii S. sanguinis S. oralis V. atypica L. casei 1T-6 S.
mutans KFINGVLSQFVLERK 15 1T-7 M. xanthus SQRIIEPVKSPQPYPGFSVS 16
1T-8 M. xanthus FSVAACGEQRAVTFVLLIEDLI 17 1T-9 M. xanthus
WAWAESPRCVSTRSNIHALAFRVEVAA 18 LT 1T-10 M. xanthus SPAGLPGDGDEA 19
1T-11 S. mutans RISE 20 S. epidermidis P. aeruginosa 1T-12 C.
xerosis FGNIFKGLKDVIETIVKWTAAK 21 C. striatum S. epidermidis S.
mutans 1T-13 S. aureus FRSPCINNNSLQPPGVYPAR 22 S. epidermidis P.
aeruginosa 1T-14 S. mutans ALAGLAGLISGK 23 S. aureus S. epidermidis
C. xerosis 1T-15 S. mutans DVILRVEAQ 24 1T-16 P. aeruginosa IDMR 25
1T-17 S. mutans NNAIVYIS 26 1T-18 S. aureus YSKTLHFAD 27 S.
epidermidis C. striatum P. aeruginosa 1T-19 S. aureus PGAFRNPQMPRG
28 S. epidermidis P. aeruginosa 1T-20 S. mutans
PALVDLSNKEAVWAVLDDHS 29 P. aeruginosa 1T-21 S. mutans
YVEEAVRAALKKEARISTEDTPVNLPSF 30 P. aeruginosa DC 1T-22 S.
epidermidis VPLDDGTRRPEVARNRDKDRED 31 P. aeruginosa 1T-23 S. mutans
PALVDLSNKEAVWAVLDDHS 32 P. aeruginosa 1T-24 P. aeruginosa
EEAEEKLAEVSQAVKRLVR 33 1T-25 S. aureus VGLDVSVLVLFFGLQLLSVLLGAMIR
34 S. epidermidis C. xerosis C. striatum P. aeruginosa 1T-26 S.
mutans LTILPTTFFAIIVPILAVAFIAYSGFKIKGI 35 S. aureus VEHKDQW S.
epidermidis C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-27
S. mutans ALFVSLEQFLVVVAKSVFALCHSGTLS 36 S. aureus S. epidermidis
C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-28 P.
aeruginosa VSRDEAMEFIDREWTTLQPAGKSHA 37 1T-29 S. mutans
GSVIKKRRKRMSKKKHRKMLRRTRVQ 38 S. aureus RRKLGK S. epidermidis C.
jeikeium C. xerosis C. striatum P. aeruginosa 1T-30 S. aureus
GKAKPYQVRQVLRAVDKLETRRKKGGR 39 S. epidermidis C. xerosis C.
striatum P. aeruginosa 1T-31 S. mutans NATGTDIGEVTLTLGRFS 40 P.
aeruginosa 1T-32 S. mutans VSFLAGWLCLGLAAWRLGNA 41 1T-33 S. aureus
VRTLTILVIFIFNYLKSISYKLKQPFENNL 42 S. epidermidis AQSMISI C.
jeikeium C. xerosis C. striatum P. aeruginosa 1T-34 S. aureus
AFWLNILLTLLGYIPGIVHAVYIIAKR 43 S. epidermidis C. jeikeium C.
xerosis C. striatum P. aeruginosa 1T-35 P. aeruginosa
EICLTLVFPIRGSYSEAAKFPVPIHIVEDG 44 TVELPK 1T-36 S. aureus
VYRHLRFIDGKLVEIRLERK 45 S. epidermidis C. jeikeium C. xerosis C.
striatum P. aeruginosa 1T-37 S. mutans YIVGALVILAVAGLIYSMLRKA 46 S.
aereus S. epidermidis C. jeikeium C. xerosis C. striatum P.
aeruginosa 1T-38 S. mutans VMFVLTRGRSPRPMIPAY 47 S. aereus S.
epidermidis C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-39
S. mutans FGFCVWMYQLLAGPPGPPA 48 P. aeruginosa 1T-40 S. mutans
QRVSLWSEVEHEFR 49 P. aeruginosa 1T-41 S. mutans
KRGSKIVIAIAVVLIVLAGVWVW 50 S. aureus S. epidermidis C. jeikeium C.
striatum P. aeruginosa 1T-42 S. aureus TVLDWLSLALATGLFVYLLVALLRADRA
51 S. epidermidis C. xerosis C. striatum P. aeruginosa 1T-43 C.
jeikium DRCLSVLSWSPPKVSPLI 52 P. aeruginosa 1T-44 S. mutans
DPALADFAAGMRAQVRT 53 S. aureus S. epidermidis C. jeikeium C.
striatum P. aeruginosa 1T-45 S. aureus WTKPSFTDLRLGFEVTLYFANR 54 S.
epidermidis C. striatum P. aeruginosa 1T-46 S. aureus
FSFKQRVMFRKEVERLR 55 S. epidermidis C. jeikeium C. xerosis C.
striatum P. aeruginosa 1T-47 S. mutans VIKISVPGQVQMLIP 56 S.
epidermidis P. aeruginosa 1T-48 S. aureus
KLQVHHGRATHTLLLQPPLCAPGTIR 57 S. epidermidis C. jeikeium C. xerosis
C. striatum P. aeruginosa 1T-49 S. aureus SLVRIHDQQPWVTRGAFIDAARTCS
58 S. epidermidis C. jeikeium P. aeruginosa 1T-50 P. aeruginosa
HSDEPIPNILFKSDSVH 59 1T-51 S. aureus GKPKRMPAEFIDGYGQALLAGA 60 P.
aeruginosa 1T-52 S. aureus DEYPAKLPLSDKGATEPRRH 61 C. xerosis P.
aeruginosa 1T-53 P. aeruginosa SDILAEMFEKGELQTLVKDAAAKANA 62 1T-54
S. epidermidis RWVSCNPSWRIQ 63 C. xerosis C. striatum P. aeruginosa
1T-55 C. xerosis NHKTLKEWKAKWGPEAVESWATLLG 64 P. aeruginosa 1T-56
C. xerosis LALIGAGIWMIRKG 65 P. aeruginosa 1T-57 P. aeruginosa
RLEYRRLETQVEENPESGRRPMRG 66 1T-58 P. aeruginosa CDDLHALERAGKLDALLSA
67 1T-59 S. aureus AVGNNLGKDNDSGHRGKKHRKHKHR 68 S. epidermidis P.
aeruginosa 1T-60 S. aureus YLTSLGLDAAEQAQGLLTILKG 69 S. epidermidis
C. jeikeium C. striatum P. aeruginosa
1T-61 P. aeruginosa HATLLPAVREAISRQLLPALVPRG 70 1T-62 S.
epidermidis GCKGCAQRDPCAEPEPYFRLR 71 P. aeruginosa 1T-63 S. aureus
EPLILKELVRNLFLFCYARALR 72 S. epidermidis C. jeikeium C. xerosis C.
striatum P. aeruginosa 1T-64 S. aureus QTVHHIHMHVLGQRQMHWPPG 73 S.
epidermidis C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-65
S. mutans HARAAVGVAELPRGAAVEVELIAAVRP 74 S. aureus S. epidermidis
C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-66 S. mutans
DTDCLSRAYAQRIDELDKQYAGIDKPL 75 S. aureus S. epidermidis C. jeikeium
C. xerosis C. striatum P. aeruginosa 1T-67 S. aureus
GQRQRLTCGRVSGCSEGPSREAAR 76 S. epidermidis C. jeikeium C. xerosis
C. striatum P. aeruginosa 1T-68 S. mutans GGTKEIVYQRG 77 S. aureus
C. jeikeium C. xerosis C. striatum P. aeruginosa 1T-69 S. mutans
ILSQEADRKKLF 78 P. aeruginosa 1T-70 S. aureus NRQAQGERAHGEQQG 79 C.
jeikeium P. aeruginosa 1T-71 P. aeruginosa KIDTNQWPPNKEG 80 1T-72
P. aeruginosa EPTDGVACKER 81 1T-73 S. pneumoniae
GWWEELLHETILSKFKITKALELPIQL 82 1T-74 S. pneumoniae
DIDWGRKISCAAGVAYGAIDGCATTV 83 1T-75 S. pneumoniae
GVARGLQLGIKTRTQWGAATGAA 84 1T-76 S. pneumoniae EMRLSKFFRDFILWRKK 85
1T-77 S. pneumoniae EMRISRIILDFLFLRKK 86 1T-78 S. pneumoniae
FFKTIFVLILGALGVAAGLYIEKNYIDK 87 1T-79 S. pneumoniae
FGTPWSITNFWKKNFNDRPDFDSDRRRY 88 1T-80 S. pneumoniae GGNLGPGFGVIIP
89 1T-81 S. pneumoniae AIATGLDIVDGKFDGYLWA 90 1T-82 S. pneumoniae
FGVGVGIALFMAGYAIGKDLRKKFGKSC 91 1T-83 S. pneumoniae
QKPRKNETFIGYIQRYDIDGNGYQSLPC 92 PQN 1T-84 S. pneumoniae
FRKKRYGLSILLWLNAFTNLVNSIHAFY 93 MTLF 1T-85 A. naeslundii
VMASLTWRMRAASASLPTHSRTDA 94 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-86 S. mitis HRKNPVLGVGRRHRAHNVA 95 S. oralis S.
salivarious 1T-87 S. mitis EAVGQDLVDAHHP 96 S. mutans S. oralis
1T-89 S. mitis HEDDKRRGMSVEVLGFEVVQHEE 97 S. mutans 1T-90 S.
gordonii RNVIGQVL 98 S. mitis S. mutans S. oralis S. sanguinis
1T-91 S. mitis TSVRPGAAGAAVPAGAAGAAGAGWR 99 S. mutans WP S. oralis
S. sanguinis 1T-92 S. mitis GQDEGQRRAGVGEGQGVDG 100 S. mutans 1T-93
S. epidermidis AMRSVNQA 101 S. gordonii S. mitis S. mutans S.
oralis S. sanguinis 1T-94 S. mitis DQVAHSGDMLVQARRRDS 102 S. mutans
S. oralis 1T-95 S. gordonii GHLLRVGGRVGGVGGVAGACAQPFGGQ 103 S.
mitis S. mutans S. oralis S. sanguinis 1T-96 S. gordonii
VAGACAQPFGGQ 104 S. mitis S. mutans S. oralis S. sanguinis 1T-97 A.
naeslundii GVAERNLDRITVAVAIIWTITIVGLGLV 105 F. nucleatum AKLG P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-98 A. naeslundii
VRSAKAVKALTAAGYTGELVNVSGGM 106 F. nucleatum KAWLGQ P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-99 S. gordonii MKAWLGQ 107 S. mitis S. mutans S.
oralis S. sanguinis 1T-100 S. gordonii LDPLEPRIAPPGDRSHQGAPACHRDPLR
108 S. mitis GRSARDAER S. mutans 1T-101 A. naeslundii
RLRVGRATDLPLTSFAVGVVRNLPDAP 109 P. gingivalis AH S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. sanguinis 1T-102 A.
naeslundii WKRLWPARILAGHSRRRMRWMVVWR 110 F. nucleatum YFAAT P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-103 A. naeslundii
AQFYEAIITGYALGAGQRIGQL 111 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. sanguinis
1T-104 S. mitis RAVAAHLQGRHHGHQVRRQRHGQR 112 1T-105 S. epidermidis
GEGLPPPVLHLPPPRMSGR 113 S. gordonii S. mitis S. mutans S. oralis
1T-106 S. gordonii DALRRSRSQGRRHR 114 S. mitis S. mutans S. oralis
S. salivarious 1T-107 A. naeslundii SPVPRFTAVGGVSRGSP 115 S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-108 S. gordonii WGPLGPERPLW 116 S. mitis S. mutans
S. oralis S. salivarious S. sanguinis 1T-109 A. naeslundii
VTTNVRQGAGS 117 S. epidermidis S. gordonii S. mitis S. mutans S.
oralis S. salivarious S. sanguinis 1T-110 A. naeslundii
LAAKTAVCVGRAFM 118 P. gingivalis S. epidermidis S. gordonii S.
mitis
S. mutans S. oralis S. sanguinis 1T-111 A. naeslundii
GRLSRREEDPATSIILLRGAYRMAVF 119 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-112 S. gordonii SDNDGKLILGTSQ 120 1T-113 S. mitis
HGAHQRTGQRLHHHRGRTVSGCRQNP 121 VAGVDPDEHR 1T-114 A. naeslundii
RQAPGPGLVTITAACSAPGSRSR 122 P. gingivalis S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. sanguinis 1T-115 A.
naeslundii LLIERFSNHH 123 F. nucleatum P. gingivalis S. epidermidis
S. gordonii S. mitis S. mutans S. oralis S. salivarious S.
sanguinis 1T-116 A. naeslundii MILHRRRDR 124 P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-117 S. mutans GPGVVGPAPFSRLPAHALNL 125 1T-118 A.
naeslundii TASPPAPSDQGLRTAFPATLLIALAALA 126 F. nucleatum RISR P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-119 S. gordonii
SPATQKAPTRAQPSRAPVQDCGDGRPT 127 S. mitis AAPDDVERLSPR S. mutans S.
oralis 1T-120 A. naeslundii DVRDRVDLAGADLCAAHATR 128 F. nucleatum
P. gingivalis S. epidermidis S. gordonii S. mitis S. mutans S.
oralis S. salivarious S. sanguinis 1T-121 S. gordonii
FAKETGFGIGGAQEGWWIIADIYGPNPF 129 S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-122 S. mitis GAIPDPVTHRVDWEEDHQTRPSR
130 1T-123 S. gordonii LVRRNAVAGRSDGLAGAEQLDLVRLQ 131 GVL 1T-124 S.
mitis LFDERNKIA 132 S. mutans S. oralis 1T-125 S. epidermidis
DAITGGNPPLSDTDGLRP 133 S. gordonii S. mutans S. oralis 1T-126 S.
gordonii QGLARPVLRRIPL 134 S. mitis S. mutans 1T-127 A. naeslundii
YDPVPKRKNKNSEGKREE 135 F. nucleatum P. gingivalis T. denticola S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-128 A. naeslundii SGSAIRMLEIATKMLKR 136 P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-129 A. naeslundii YDKYIKYLSIQPPFIVYFI 137 P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-130 A. naeslundii
QKIIDMSKFLFSLILFIMIVVIYIGKSIGG 138 F. nucleatum
YSAIVSSIMLELDTVLYNKKIFFIYK P. gingivalis S. epidermidis S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-131 A.
naeslundii DEVWKMLGI 139 F. nucleatum P. gingivalis T. denticola S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-132 A. naeslundii YSKKLFEYFYFIIFILIRYLIFYKIIQNKNY 140 F.
nucleatum YINNIAYN P. gingivalis S. epidermidis S. gordonii S.
mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-133 A.
naeslundii YFIKDDNEALSKDWEVIGNDLKGTIDK 141 P. gingivalis YGKEFKVR
S. epidermidis S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-134 A. naeslundii SRLVREIKKKCRKS 142 F.
nucleatum P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-135 A. naeslundii
FESLLPQATKKIVNNKGSKINKIF 143 P. gingivalis S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-136 A. naeslundii ELLTQIRLALLYSVNEW 144 F. nucleatum P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-137 A. naeslundii
PLNFYRAVKENRLPLSEKNINDFTNIKL 145 F. nucleatum
KVSPKLINLLQESSIFYNFSPKKRNTN P. gingivalis S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-138 A. naeslundii YPNEYCIFLENLSLEELKEIKAINGETLN 146 F. nucleatum
LEEIINERKNLKD P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-139 A. naeslundii
AVAGAAVGALLGNDARSTAVGAAIGG 147 S. gordonii ALGAGAGELTKNK S. mitis
S. mutans S. oralis 1T-140 A. naeslundii
IKGTIAFVGEDYVEIRVDKGVKLTFRKS 148 F. nucleatum AIANVINNNQQ P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-141 F. nucleatum
KKFIILLFILVQGLIFSATKTLSDIIAL 149 P. gingivalis
S. epidermidis S. gordonii S. mitis S. mutans S. oralis S.
sanguinis 1T-142 A. naeslundii FTQGIKRIVLKRLKED 150 F. nucleatum P.
gingivalis T. denticola S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-143 A. naeslundii
MPKRHYYKLEAKALQFGLPFAYSPIQL 151 F. nucleatum LK P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-144 A. naeslundii IIELHPKSWTQDWRCSFL 152 F.
nucleatum P. gingivalis T. denticola S. gordonii S. mitis S. mutans
S. oralis S. salivarious S. sanguinis 1T-145 S. mitis
VEAGKRNISLENIEKISKGLGISISELFKY 153 S. mutans IEEGEDKIG S. oralis
1T-146 A. naeslundii RNSADNQTKIDKIRIDISLWDEHLNIVK 154 F. nucleatum
QGK P. gingivalis T. denticola S. gordonii S. mitis S. mutans S.
oralis S. salivarious S. sanguinis 1T-147 A. naeslundii
GVENRRFYERDVSKVSMMTSEAVAPR 155 F. nucleatum GGSK P. gingivalis T.
denticola S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-148 A. naeslundii IVELDDTTILERALSMLGEANA 156 F.
nucleatum P. gingivalis T. denticola S. gordonii S. mitis S. mutans
S. oralis S. salivarious S. sanguinis 1T-149 A. naeslundii
SVRAVKPIDETVARHFPGDFIVN 157 F. nucleatum P. gingivalis T. denticola
S. gordonii S. mitis S. mutans S. oralis S. salivarious S.
sanguinis 1T-150 A. naeslundii YINRRLKKAFSDADIKEAPAEFYEELRR 158 F.
nucleatum VQYV P. gingivalis T. denticola S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-151 A. naeslundii
SVRAVKPIDEIVAWHFPGDFIVN 159 F. nucleatum P. gingivalis T. denticola
S. gordonii S. mitis S. mutans S. oralis S. salivarious S.
sanguinis 1T-152 A. naeslundii YVSADESAYNHIVTDDIPLADRRIEAVQQ 160 F.
nucleatum P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-153 A. naeslundii
YIACPGYFY 161 F. nucleatum P. gingivalis S. epidermidis S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-154 P.
gingivalis YFSFLEIVGMARR 162 1T-155 A. naeslundii
LKLAFGVYPFQAMSQSDTAVSERNVL 163 F. nucleatum WR P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-156 A. naeslundii GRFQISIRGEEKSKVKVQGKGTFTDRNTT 164
F. nucleatum P. gingivalis T. denticola S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-157 A. naeslundii
RRFRKTTENREKSKNKKAVLGLSTTST 165 F. nucleatum ASY P. gingivalis T.
denticola S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-158 A. naeslundii WENKPSPLGSIKKLQGLVYRLIGYRHF 166
F. nucleatum WV P. gingivalis S. epidermidis S. gordonii S. mitis
S. mutans S. oralis S. salivarious S. sanguinis 1T-159 P.
gingivalis IFSLHHFALICSEMGTFAVSKRAKYKWE 167 VL 1T-160 A. naeslundii
AQYKYINKLLN 168 F. nucleatum P. gingivalis T. denticola S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-161 A.
naeslundii NKVLQVEVMWDGSVVGRPAGVISIKSS 169 F. nucleatum KKG P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-162 A. naeslundii
QKAKEESDRKAAVSYNGFHRVNVVSIPK 170 F. nucleatum P. gingivalis T.
denticola S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-163 A. naeslundii MENILIYIPMVLSPFGSGILLFLGKDRRY 171
F. nucleatum ML P. gingivalis S. epidermidis S. gordonii S. mitis
S. mutans S. oralis S. salivarious S. sanguinis 1T-164 A.
naeslundii KKSHSQGKRKLKDLNSAYKIDNQLHYA 172 F. nucleatum LR P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-165 A. naeslundii
CYDSFDFSIFVTFANRMKLSVGS 173 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-166 A. naeslundii AQSAGQIKRKSKVRIHV 174 F.
nucleatum P. gingivalis S. epidermidis
S. gordonii S. mitis S. mutans S. oralis S. salivarious S.
sanguinis 1T-167 A. naeslundii SRMSEHSPAGLVFEVGPMDKGSFIILDS 175 F.
nucleatum YHPTVKK P. gingivalis S. epidermidis S. gordonii S. mitis
S. mutans S. oralis S. salivarious S. sanguinis 1T-168 A.
naeslundii ELHRIMSTEKIGAVTKMNFDTAPIMSILP 176 F. nucleatum
IDIYPKEVGIGS P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-169 A. naeslundii
FARVRRLHQNRILTQPLTNLKYCLRQPI 177 F. nucleatum YSD P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-170 P. gingivalis AYGKVFSMDIMLSENDKLIVLRISHHSA 178
WH 1T-171 A. naeslundii SVRAVKPIDKTVARHFPGDFIVN 179 F. nucleatum P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-172 A. naeslundii FEGLKNLLGDDII 180
F. nucleatum P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-173 A. naeslundii
LFRKEDQEHVLL 181 F. nucleatum P. gingivalis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-174 A. naeslundii
SGGSDTDGSSSGEPGSHSGDL 182 F. nucleatum P. gingivalis T. denticola
S. gordonii S. mitis S. mutans S. oralis S. salivarious S.
sanguinis 1T-175 A. naeslundii GEPGSHSGDL 183 F. nucleatum P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-176 A. naeslundii
PVGDIMSGFLRGANQPRFLLDHISFGS 184 P. gingivalis S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-177 P. gingivalis GTNVPTQILGYSREERFDYEPAPEQR 185 S. gordonii S.
mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-178 A.
naeslundii LLASHPERLSLGVFFVYRVLHLLLENT 186 F. nucleatum P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-179 A. naeslundii TCYPLIQRKTDRAYEA
187 F. nucleatum P. gingivalis T. denticola S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-180 A. naeslundii
VVFGGGDRLV 188 F. nucleatum P. gingivalis T. denticola S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-181 A.
naeslundii YGKESDP 189 F. nucleatum P. gingivalis T. denticola S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-182 A. naeslundii LTASICRQWNDNSTPYQR 190 F. nucleatum P.
gingivalis T. denticola S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-183 A. naeslundii
PLRSFVAEKAEHAFRVVRIADFDFGHS 191 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-184 A. naeslundii ALLVLNLLLMQFFFGKNM 192 F.
nucleatum P. gingivalis T. denticola S. gordonii S. mitis S. mutans
S. oralis S. salivarious S. sanguinis 1T-185 A. naeslundii
HYHFLLEFGFHKGDYLE 193 F. nucleatum P. gingivalis T. denticola S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-188 S. sanguinis HRKDVYKK 194 1T-190 A. naeslundii
IQIIVNAFVEKDKTGAVIEVLYASNNHE 195 F. nucleatum KVKAKYEELVAIS P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-192 S. sanguinis ILVLLALQVELDSKFQY
196 1T-193 S. sanguinis LMIFDKHANLKYKYGNRSFGVEAIM 197 1T-195 S.
mutans AASGFTYCASNGVWHPY 198 1T-196 F. nucleatum
KPEKEKLDTNTLMKVVNKALSLFDRLL 199 S. sanguinis IKFGA 1T-197 A.
naeslundii TEILNFLITVCADRENWKIKHGLSDSVL 200 F. nucleatum
LIFFARFTGAEYW P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-198 P. gingivalis
MPVSKKRYMLSSAYATALGICYGQVAT 201 S. epidermidis
DEKESEITAIPDLLDYLSVEEYLL S. gordonii S. mitis S. mutans S. oralis
S. sanguinis 1T-199 S. sanguinis RAGRIKKLSQKEAEPFEN 202 1T-200 A.
naeslundii MRFKRFDRDYALSGDNVFEVLTASCDV 203 F. nucleatum
IERNLSYREMCGLMQ S. epidermidis S. gordonii S. mitis
S. mutans S. oralis S. salivarious S. sanguinis 1T-201 S. sanguinis
KRKHENVIVAEEMRVIKN 204 1T-202 A. naeslundii
LCRLEKLCKQFLRQDKVVTYYLMLPYK 205 F. nucleatum RAIEAFYQELKERS P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-203 A. naeslundii
YPFCLATVDHLPEGLSVTDYERVQRLV 206 F. nucleatum SQFLLNKEER P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-207 F. nucleatum
SPLEKYGTGSMTALTFLLGCCLLVLSKK 207 S. sanguinis SR 1T-208 Unanalyzed
KRKRWAILTLFLAGLGAVGIVLATF 208 1T-215 S. sanguinis
VCFKDISVFLSPFRGQEVLFCGKAKHSL 209 IYVIGT 1T-216 S. sanguinis
FFLNVIAIRIPHF 210 1T-217 F. nucleatum MLSNVLSRSVVSPNVDIPNSMVILSPLLI
211 S. sanguinis SISNYH 1T-218 F. nucleatum KLIFAALGLVFLLIGLRDSRSK
212 S. sanguinis 1T-219 S. sanguinis RNINVSATFITEKSLV 213 1T-221 A.
naeslundii DIGRIIGKKGRTITAIRSIVYSVPTQGKK 214 F. nucleatum VRLVIDEK
P. gingivalis S. epidermidis S. gordonii S. mitis S. mutans S.
oralis S. salivarious S. sanguinis 1T-222 F. nucleatum
RIEASLISAIMFSMFNAIVKFLQK 215 S. sanguinis 1T-223 A. naeslundii
NQKMEINSMTSEKEKMLAGHFHNEAN 216 F. nucleatum FAVIFKYSLFYNFF P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-225 A. naeslundii
RRSLGNSASFAEWIEYIRYLHYIIRVQFI 217 F. nucleatum HFFSKNKKI P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-226 A. naeslundii
KLQEKQIDRNFERVSGYSTYRAVQAAK 218 F. nucleatum AKEKGFISLEN S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-228 A. naeslundii IFKLFEEHLLYLLDAFYYSKIFRRLKQGL 219
F. nucleatum YRRKEQPYTQDLFRM P. gingivalis S. epidermidis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-230 A. naeslundii EFLEKFKVLKQPRKANNISKNRVAMIFL 220 F. nucleatum
TIHKSRGFLSSPY P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-233 A. naeslundii
TDQELEHLIVTELESKRLDFTYSKDITEF 221 P. gingivalis FDEAFPEYDQNY S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-234 A. naeslundii DNFYLILKMEERGKSKKTSQTRGFRAFF 222
F. nucleatum DIIRKKIKKEDGK P. gingivalis S. epidermidis S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-237 S.
sanguinis EDPVPNHFTLRRNKKEKPSKS 223 1T-238 A. naeslundii
IFNRRKFFQYFGLSKEAMVEHIQPFILDI 224 F. nucleatum WQIHLF P. gingivalis
S. epidermidis S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-239 A. naeslundii
ADDLLNKRLTDLIMENAETVKTIDLDN 225 S. gordonii SD S. mitis S. mutans
S. oralis S. sanguinis 1T-240 A. naeslundii
VILGNGISNIAQTLGQLPNIAWVWIYMV 226 F. nucleatum LIAALLEESNVC P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-242 F. nucleatum
KQVQNTTLIICGTVLLGILFKSYLKSQKSV 227 S. sanguinis 1T-243 A.
naeslundii SENIARFAAAFENEQVVSYARWFRRSW 228 P. gingivalis RGSGSSSRF
S. epidermidis S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-248 S. sanguinis IGGALNSCG 229 1T-249
F. nucleatum VFSVLKHTTWPTRKQSWHDFISILEYSA 230 S. sanguinis
FFALVIFIFDKLLTLGLAELLKRF 1T-250 S. mitis
LVQGDTILIENHVGTPVKDDGKDCLIIR 231 S. mutans EADVLAVVND S. oralis
1T-252 F. nucleatum MKKNLKRFYALVLGFIIGCLFVSILIFIGY 232 S. sanguinis
1T-253 A. naeslundii KTKESLTQQEKKFLKDYDRKSLHHFRD 233 F. nucleatum
ILTYCFILDKLTNK P. gingivalis S. epidermidis S. gordonii S. mitis S.
mutans S. oralis S. salivarious S. sanguinis 1T-256 S. sanguinis
KGKSLMPLLKQINQWGKLYL 234 1T-257 A. naeslundii
IILAKAADLAEIERIISEDPFKINEIANYDI 235 F. nucleatum IEFCPTKSSKAFEKVLK
P. gingivalis S. epidermidis S. gordonii S. mitis S. mutans S.
oralis S. salivarious S. sanguinis 1T-258 A. naeslundii
TINIDDKVLDYLKKINSKAITIDLIGCAS 236 F. nucleatum P. gingivalis T.
denticola S. mitis S. mutans S. oralis 1T-259 F. nucleatum
EKLKKILLKLAVCGKAWYTL 237 P. gingivalis T. denticola S. mitis S.
mutans S. oralis S. sanguinis 1T-260 A. naeslundii
NILYFIHDENQWEPQKAEIFRGSIKHCA 238 P. gingivalis WLSS S. epidermidis
S. gordonii S. mitis S. mutans S. oralis S. sanguinis 1T-261 F.
nucleatum SFEKNKIENNLKIAQAYIYIKPKPRICQA 239 S. mutans S. oralis S.
sanguinis 1T-262 A. naeslundii LSLPLIVLTKSI 240 F. nucleatum P.
gingivalis S. epidermidis S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-263 A.
naeslundii FIAVSFTGNPATFKLVIGCKADN 241 F. nucleatum P. gingivalis
S. epidermidis S. gordonii S. mitis S. oralis S. salivarious S.
sanguinis 1T-264 S. sanguinis LEGKFYMAEDFDKTPECFKDYV 242 1T-265 A.
naeslundii GMFENLLMINFQIMNDLKIEIVVKDRIC 243 F. nucleatum AV P.
gingivalis S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-266 S. sanguinis RAGTWLVVDEIR 244
1T-267 A. naeslundii RIKEERKNRSYKFFIWRLFDEKTGFI 245 F. nucleatum P.
gingivalis T. denticola S. mitis S. mutans S. oralis S. sanguinis
1T-268 F. nucleatum PITPKKEKCGLGTYAPKNPVFSKSRV 246 S. mutans S.
oralis S. sanguinis 1T-269 F. nucleatum PLYVAAVEKINTAKKH 247 S.
mutans S. oralis S. sanguinis 1T-270 F. nucleatum VHEFDIQKILQNR 248
S. mutans S. oralis S. sanguinis 1T-271 A. naeslundii
FLIQKFLLIKTFPPYRKKYVVIVSQTGTA 249 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-272 F. nucleatum QLAPIDKQLKAVKKIAFYESESTAAKAV 250
S. mutans TVA S. oralis S. sanguinis 1T-273 F. nucleatum
YNEPNYKWLESYKIYKQRCEDRTGMY 251 P. gingivalis YTEET T. denticola S.
mitis S. mutans S. oralis 1T-274 F. nucleatum
ETTTEINAIKLHRIKQRSPQGTRRVN 252 S. mutans S. oralis S. sanguinis
1T-275 A. naeslundii QVLKNFSISRRYKINNPFFKILLFIQLRTL 253 F.
nucleatum P. gingivalis T. denticola S. epidermidis S. gordonii S.
mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-276 A.
naeslundii ILTLLILGSIGFFILKIKLKLGRF 254 F. nucleatum P. gingivalis
S. epidermidis S. gordonii S. mitis S. mutans S. oralis S.
sanguinis 1T-277 A. naeslundii IYYMRFVNKPLEKTFFKI 255 F. nucleatum
P. gingivalis T. denticola S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-278 A. naeslundii
SINSSAGIQPHCLSSSFVLRTKHCFY 256 F. nucleatum P. gingivalis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-279 A. naeslundii FVLRTKHCFY 257 F. nucleatum P. gingivalis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-280 A. naeslundii TNNKNKVIIKAIKFKNKDFINLDLFIYRR 258 F. nucleatum
P. gingivalis T. denticola S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-281 A. naeslundii
KYEKLTKENLFIRNSGNMCVFIYFLFFG 259 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-282 F. nucleatum ISLVFPAYT 260 P. gingivalis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-283 A. naeslundii LCTKLEDKQRGRIPAELFIISPIKILERND 261 F.
nucleatum AL P. gingivalis T. denticola S. epidermidis S. gordonii
S. mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-284 A.
naeslundii FQYYFSLKRV 262 F. nucleatum P. gingivalis S. gordonii S.
mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-285 A.
naeslundii FFPYYLADFYKQLKFLNEYQTKNKDKV 263 F. nucleatum VEFK P.
gingivalis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-286 S. sanguinis LGFFNNKADLVKADTERDNRMSSLKIK 264 DL
1T-287 P. gingivalis KGYPLPFQYRLNNH 265 T. denticola S. gordonii S.
mitis S. mutans S. oralis S. salivarious S. sanguinis 1T-288 F.
nucleatum RWVGGEPSADIYLSAKDTKT 266 S. gordonii S. salivarious S.
sanguinis 1T-289 F. nucleatum EPSADIYLSAKDTKT 267 P. gingivalis S.
gordonii S. mitis S. mutans S. oralis S. sanguinis 1T-290 A.
naeslundii IINQLNLILLRLMEILIL 268 F. nucleatum P. gingivalis S.
gordonii S. mitis S. mutans S. oralis S. salivarious S. sanguinis
1T-291 A. naeslundii DMKIIKLYIKILSFLFIKYCNKKLNSVKL 269 F. nucleatum
KA P. gingivalis T. denticola S. mitis S. mutans S. oralis 1T-292
A. naeslundii IINQLNLILLRLMEILIL 270 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S.
salivarious
S. sanguinis 1T-293 A. naeslundii HVEDCFLLSNARTTAIHGRANPARGEPR 271
F. nucleatum TRSE P. gingivalis S. epidermidis S. gordonii S. mitis
S. mutans S. oralis S. salivarious S. sanguinis 1T-294 T. denticola
YDKIADGVFKIGKRGVL 272 1T-295 S. mitis KYKLKKIIL 273 S. salivarious
S. sanguinis 1T-296 A. naeslundii EYSQQSFKAKPCSERGVLSP 274 F.
nucleatum P. gingivalis S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-297 A. naeslundii
RSLRLNNALTKLPKLWYNRIKEAFYAY 275 F. nucleatum NDYDK T. denticola S.
mitis S. mutans S. oralis 1T-298 A. naeslundii
ILNKKPKLPLWKLGKNYFRRFYVLPTFLA 276 F. nucleatum P. gingivalis T.
denticola S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-299 A. naeslundii SMLTSFLRSKNTRSLKMYKDVHF 277 F.
nucleatum S. epidermidis S. gordonii S. mitis S. mutans S. oralis
S. salivarious S. sanguinis 1T-300 A. naeslundii
PLIISKAQIKMSGDILGSCFKLFYLRPFF 278 F. nucleatum P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-301 F. nucleatum SKLPRVLDASLKL 279 S. gordonii S.
sanguinis 1T-302 A. naeslundii IIIILPKIYLVCKTV 280 P. gingivalis S.
epidermidis S. gordonii S. mitis S. mutans S. oralis S. salivarious
S. sanguinis 1T-303 A. naeslundii LDYENMDCKKRIRI 281 F. nucleatum
P. gingivalis S. gordonii S. mitis S. mutans S. oralis S.
salivarious S. sanguinis 1T-304 P. gingivalis
STAGEASRRTASEASRRTAAKLRG 282 TT-305 F. nucleatum
ARNALNMRDVPVDAAIIGIIDGMDEE 283 TT-306 F. nucleatum
KILNEAEGKLLKVIEKNGEIDIEEI 284 TT-307 F. nucleatum
NGDKKAKEELDKWDEVIKELNIQF 285 TT-308 F. nucleatum
GLVIIPNLIALIILFSQVRQQTKDYFSNPK 286 LSSR TT-309 F. nucleatum
EPLPLTKYDKKDTEMKKVFKEILAGKV 287 GYEKEEE TT-310 F. nucleatum
TKLKKNNKLLSAKKENTLHTKDK 288 TT-311 S. mutans AIFDAMHNL 289 S.
sobrinus PVCFBP2461 P. fluorescens
DLys-Dorn-Gly-DThr-Thr-Gln-Gly-DSer- 290 cDOrn CHA0 P. fluorescens
Asp-DOrn-Lys-c(Thr-Ala-Ala-DOrn-Lys) 291 CFBP2461 P. putida
Asp-Lys-DAsp-Ser-DThr-DAla-Thr-DLys- 292 cOrn NCPPB2192 P. tolaasii
DSer-Lys-Ser-DSer-Thr-DSer-Orn-Thr- 293 DSer-cDOrn PyC-E P.
aeruginosa DSer-Arg-DSer-Orn-c(Lys-Orn-Thr-Thr) 294 PyR P.
aeruginosa DSer-Dab-Orn-DGln-Gln-DOrn-Gly 295 PyPaTII P. aeruginosa
DSer-DOrn-Orn-Gly-DThr-Ser-cOrn 296 Py Pap P. aptata
DAla-Lys-Thr-DSer-Orm-cOrn 297 Py Pau P. aureofaciens
DSer-DOrn-Gly-DThr-Thr-Gln-Gly-DSer- 298 cDOrn Ps P. fluorescens
Lys-DAsp-Ala-DThr-Ala-cDOrn 299 Py I-III P. fluorescens
Asn-DOrn-Lys-c(Thr-DAla-DAla-DOrn- 300 Lys) Py Gm P. fluorescens
DAla-Lys-Gly-Gly-Asp-DGln-DSer-Ala- 301 DAla-DAla-Ala-cOrn Py Pf 12
P. fluorescens DSer-Lys-Gly-Orn-DSer-Ser-Gly-c(Lys- 302
DOrn-Glu-Ser) Py Pf P. fluorescens
c(DSer-Dab)-Gly-Ser-Asp-Ala-Gly-DAla- 303 2798 Gly-cOrn Py Pf P.
fluorescens Ser-Lys-Gly-Orn-c(Lys-DOrn-Ser) 304 13525 Py Pf P.
fluorescens DAla-DLys-Gly-Gly-Asp-DGln-Dab-Ser- 305 17400 DAla-cOrn
Py 51W P. fluorescens DAla-DLys-Gly-Gly-DAsp-DGln-DSer-Ala- 306
Gly-DThr-cOrn Py 9AW P. fluorescens DSer-Lys-His-DThr-Ser-cOrn 307
Ps A225 P. fluorescens DSer-DAla-DOrn-Gly-c(DSer-DAsp-DSer- 308
DThr) Py Pf 1.3 P. fluorescens
DAla-DLys-Gly-Gly-Asp-c(DGln-Dab)-Gly- 309 Ser-cOrn Py Pf P.
fluorescens DSer-Lys-Gly-Orn-Ser-DSer-Gly-c(Lys- 310 18.1 DOrn-Ser)
Py Pf P. fluorescens DSer-DOrn-Ala-Gly-DThr-Ala-cOrn 311 PL7 Py Pf
P. fluorescens DLys-DOrn-Ala-Gly-DThr-Ser-cOrn 312 PL8 Py Pf P.
fluorescens DSer-DSer-Orn-DSer-DSer-c(DSer-Orn- 313 BTP7 Lys-Lys)
Ps 589A P. putida Asp-Lys-Asp-DSer-Thr-DAla-DGlu-DSer- 314 cOrn Py
Pp 1,2 P. putida Ser-Thr-DSer-Orn-Asp-DGln-Dab-Ser- 315 DThr-cOrn
Py Pp P. putida Asp-DOrn-DDab-Thr-Gly-DSer-Ser-Asp- 316 C2,3 Thr Py
G4R P. putida Asp-Orn-DAsp-Dab-Gly-Ser-cOrn 317 Py P. putida
Asp-DOrn-DDab-Thr-Gly-DSer-DSer-Thr- 318 PpBTP16 Asp Py P. putida
DSer-DAla-DOrn-Gly-DAla-DAsp-c(DSer- 319 Pp39167 DThr) iPy Pp P.
putida Asp-Ala-Asp-DOrn-Ser-cOrn 320 BTP1 Py P. tolaasii
DSer-Lys-Ser-DSer-Thr-DSer-Orn-Thr- 321 PT2192 DSer-Orn Ps 7SR1
Pseudomonas spp. DSer-DAsp-DThr-c(DSer-D-Orn-Ala-Gly- 322 DSer) Ps
A214 Pseudomonas spp. DSer-DAla-Gly-DSer-DAla-DAsp-DThr- 323 DOrn
Azoverdin Pseudomonas spp. Hse-DHse-Dab-DOrn-DSer-Orn 324 A.
macrocytogenes PF-S024 Corynebacteria SKRGRKRKDRRKKKANHGKRPNS 325
spp. PF-001 S. epidermidis MNNWIIVAQLSVTVINEIIDIMKEKQKG 326 M.
luteus GK P. mirabilis E. coli P. aeruginosa C. albicans MRSA E.
faecalis C. jeikeium PF-002 S. epidermidis NDDAQ 327 P. mirabilis
C. albicans C. jeikeium C. jejuni PF-003 S. epidermidis
MNNWIKVAQISVTVINEVIDIMKEKQN 328 M. luteus GGK P. mirabilis C.
albicans MRSA C. jeikeium PF-004 S. epidermidis
ARLSKAIIIAVIVVYHLDVRGLF 329 B. subtilis B. fragilis E. coli P.
aeruginosa C. albicans S. pneumoniae E. faecalis C. jeikeium PF-005
S. epidermidis MESIFKIKLMNGICRSENMNMKKKNKG 330 E. coli EKI MRSA S.
pneumoniae E. faecalis PF-006 S. epidermidis MGIIAGIIKFIKGLIEKFTGK
331
M. luteus E. coli P. aeruginosa MRSA E. faecalis C. jeikeium C.
jejuni PF-007 S. epidermidis MGIIAGIIKVIKSLIEQFTGK 332 M. luteus E.
coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-008 S. epidermidis MIEIGSIAYLNGGSKKYNHILNQENR 333 M.
luteus MRSA C. jejuni PF-009 M. luteus SKKYNHILNQENR 334 P.
mirabilis C. albicans PF-010 S. epidermidis
MDIDVNKLLQAFVYFKSFEKLRHNNS 335 M. luteus E. coli C. albicans PF-011
M. luteus MFCYYKQHKGDNFSIEEVKNIIADNEM 336 E. coli KVN P. aeruginosa
S. pneumoniae C. jeikeium PF-012 S. epidermidis
WRGPNTEAGGKSANNIVQVGGAPT 337 M. luteus P. mirabilis E. coli P.
aeruginosa MRSA S. pneumoniae C. jeikeium C. jejuni PF-013 M.
luteus LIQKGLNQTFIVVIRLNNFIKKS 338 P. mirabilis E. coli P.
aeruginosa MRSA S. pneumoniae C. jeikeium C. jejuni PF-014 E. coli
HPTDNKHN 339 C. jeikeium PF-015 E. faecalis SIDKRNLYNLKYYE 340 C.
jeikeium PF-016 S. epidermidis RKQYDDLSFNFLY 341 E. faecalis C.
jeikeium PF-017 E. coli ESIIE 342 PF-018 E. coli YYKTYFKEV 343 C.
jeikeium PF-020 S. epidermidis MKIILLLFLIFGFIVVVTLKSEHQLTLFSI 344
M. luteus C. albicans MRSA S. pneumoniae E. faecalis PF-021 S.
epidermidis FSLNFSKQKYVTVN 345 M. luteus P. mirabilis E. coli C.
albicans E. faecalis C. jeikeium PF-022 M. luteus
MINELKNKNSGIMNNYVVTKESKL 346 P. mirabilis E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-023 M. luteus MTKNTIISLENEKTQINDSENESSDLRKAK 347 C. jeikeium
PF-024 M. luteus DLRKAK 348 C. albicans MRSA E. faecalis C.
jeikeium PF-025 S. epidermidis LLIIFRLWLELKWKNKK 349 M. luteus P.
mirabilis E. coli P. aeruginosa MRSA E. faecalis C. jejuni PF-026
S. epidermidis SIHFIN 350 M. luteus P. mirabilis C. albicans MRSA
E. faecalis C. jeikeium PF-027 M. luteus HNARKYLEFISQKIDGDKLTKEDSL
351 MRSA E. faecalis C. jejuni PF-028 S. epidermidis
ALDCSEQSVILWYETILDKIVGVIK 352 M. luteus MRSA PF-029 S. epidermidis
NSTNE 353 M. luteus C. albicans C. jejuni PF-030 S. epidermidis
MTCHQAPTTTHQSNMA 354 M. luteus P. mirabilis E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-031 M. luteus MPHHSTTSSRIVVPAHQSNMASTPNLSI 355 C. albicans TP
PF-033 S. epidermidis MFIFKTTSKSHFHNNVKSLECIKIPINKNR 356 M. luteus
E. coli P. aeruginosa C. albicans MRSA S. pneumoniae PF-034 M.
luteus EPKKKHFPKMESASSEP 357 PF-035 S. epidermidis SFYESY 358 M.
luteus E. coli C. albicans MRSA C. jeikeium C. jejuni PF-036 S.
epidermidis ILNRLSRIVSNEVTSLIYSLK 359 M. luteus P. mirabilis E.
coli C. albicans MRSA S. pneumoniae C. jejuni PF-037 S. epidermidis
MTKKRRYDTTEFGLAHSMTAKITLHQA 360 M. luteus LYK P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-038 M.
luteus MAYKDEGKETKFAVKGYKD 361 PF-039 P. mirabilis MLEEKNKSL 362 C.
jeikeium PF-040 S. epidermidis MIHLTKQNTMEALHFIKQFYDMFFILNF 363 M.
luteus NV P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-041 MRSA ELLVILPGFI
364 PF-042 S. epidermidis LLLSYFRYTGALLQSLF 365 M. luteus P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium PF-043 M. luteus MIKNETAYQMNELLVIRSAYAK 366 C.
jejuni PF-044 S. epidermidis KLKKYIHKPD 367 M. luteus MRSA C.
jeikeium PF-045 S. epidermidis LDINDYRSTY 368 E. coli E. faecalis
C. jejuni PF-046 E. coli LDFYLTKHLTLML 369 E. faecalis C. jeikeium
PF-047 S. mutans NQEPSLQQDKEQKDNKG 370 PF-048 S. epidermidis
LYFAFKKYQERVNQAPNIEY 371 M. luteus E. coli MRSA C. jeikeium C.
jejuni PF-049 S. epidermidis AYYLKRREEKGK 372 MRSA C. jeikeium C.
jejuni PF-050 S. epidermidis SYYLKRREEKGK 373
M. luteus E. coli C. jeikeium PF-051 S. epidermidis
RFFNFEIKKSTKVDYVFAHVDLSDV 374 M. luteus P. aeruginosa C. albicans
MRSA S. pneumoniae E. faecalis PF-052 S. epidermidis
QELINEAVNLLVKSK 375 M. luteus E. coli MRSA E. faecalis C. jeikeium
C. jejuni PF-053 S. epidermidis KLFGQWGPELGSIYILPALIGSIILIAIVTL 376
M. luteus ILRAMRK E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-054 S. epidermidis VSISRFIGGGHVFNGNNKRNL
377 E. coli PF-055 S. mutans GHVFNGNNKRNL 378 PF-056 S. epidermidis
AEQLFGKQKQRGVDLFLNRLTIILSILFF 379 M. luteus VLMICISYLGM P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium PF-057 S. epidermidis TMIVISIPRFEEYMKARHKKWM
380 M. luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA
S. pneumoniae E. faecalis C. jeikeium C. jejuni PF-058 S.
epidermidis FADQSQDNA 381 M. luteus E. coli C. albicans MRSA C.
jeikeium C. jejuni PF-060 E. coli HSSHL 382 C. albicans C. jeikeium
PF-061 S. epidermidis GYNSYKAVQDVKTHSEEQRVTAKK 383 S. pneumoniae
PF-062 S. epidermidis MKKKRINNDILGRMIYSSSIDKRNLYNL 384 M. luteus
KYYE E. coli P. aeruginosa MRSA S. pneumoniae E. faecalis C.
jeikeium PF-063 S. epidermidis IAAIIVLVLFQKGLLQIFNWILIQLQ 385 M.
luteus E. coli P. aeruginosa MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-064 E. coli DYYGKE 386 PF-065 M. luteus
LEKNTRDNYFIHAIDRIYINTSKGLFPES 387 E. coli ELVAWG P. aeruginosa C.
albicans MRSA S. pneumoniae C. jeikeium C. jejuni PF-066 M. luteus
IKGTVKAVDETTVVITVNGHGTELTFEK 388 E. coli PAIKQVDPS C. jeikeium
PF-067 S. epidermidis DLIVKVHICFVVKTASGYCYLNKREAQ 389 M. luteus AAI
P. mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
E. faecalis C. jeikeium C. jejuni PF-068 S. epidermidis
SHLINNFGLSVINPSTPICLNFSPVFNLLT 390 M. luteus VYGITCN P. mirabilis
E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-069 E. faecalis FDPVPLKKDKSASKHSHKHNH 391 C. jejuni
PF-070 S. epidermidis SMVKSEIVDLLNGEDNDD 392 C. jejuni PF-071 S.
epidermidis HCVIGNVVDIANLLKRRAVYRDIADVIK 393 E. coli MR P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni PF-073 S. epidermidis CPSVTMDACALLQKFDFCNNISHFRHFF 394 M.
luteus AIKQPIER P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis PF-074 S. epidermidis RDIHPIYFMTKD 395 M. luteus MRSA
PF-075 M. luteus FVNSLIMKDLSDNDMRFKYEYYNREKDT 396 E. coli P.
aeruginosa MRSA C. jeikeium PF-076 S. epidermidis
LYQYELLSKEEYLKCTLIINQRRNEQK 397 M. luteus E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-097 C. jeikeium QPTQGEQGTRPRRPTPMRGLLI 398 PF-099 S. epidermidis
EIIAYLEGRFANA 399 M. luteus E. coli C. jeikeium PF-101 S. mutans
DPVPERQEQACACHRTAKPGK 400 PF-104 MRSA ERTAVNDLWI 401 C. jeikeium
PF-123 M. luteus TTRPQVAEDRQLDDALKETFPASDPISP 402 E. coli PF-124 S.
epidermidis MADGQIAAIAKLHGVPVATRNIRHFQSF 403 M. luteus GVELINPWSG
P. mirabilis E. coli P. aeruginosa C. albicans MRSA E. faecalis C.
jejuni PF-125 S. epidermidis YVVGALVILAVAGLIYSMLRKA 404 M. luteus
P. mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
E. faecalis C. jejuni PF-126 S. epidermidis
FSPEAFGIGAAGVLGSFVTGLLIGWVAS 405 M. luteus LLRKAK P. mirabilis E.
coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-127 S. epidermidis MLRYLSLFAVGLATGYAWGWIDGLAA
406 M. luteus SLAV E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-128 M. luteus GIKVVAARFEEIQFSENFDSIILA
407 P. aeruginosa E. faecalis PF-129 S. epidermidis
MKLLARDPWVCAWNDIW 408 MRSA E. faecalis C. jeikeium C. jejuni PF-130
E. faecalis LQRSDEESMPRRHEKYS 409 C. jeikeium C. jejuni PF-131 S.
epidermidis RRAAARTKGNRR 410 E. coli MRSA C. jeikeium PF-132 S.
epidermidis RPGDGAAEQGRSR 411
C. jeikeium PF-133 S. epidermidis GDPTAGQKPVECP 412 C. jeikeium C.
jejuni M. smegmatis PF-134 S. epidermidis GKAMKRQDCSAL 413 C.
jeikeium PF-135 S. epidermidis PPARPARIPQTPTLHGASLFRQRS 414 M.
luteus E. coli P. aeruginosa MRSA C. jeikeium M. smegmatis PF-136
S. epidermidis LRGRVGRITACGYPP 415 M. luteus P. mirabilis E. coli
MRSA E. faecalis C. jeikeium C. jejuni M. smegmatis PF-137 S.
epidermidis VLGKGHDLLDVGKTALKSRVFAWLGGS 416 P. mirabilis S.
pneumoniae C. jeikeium C. jejuni PF-138 S. epidermidis AVHHSLLFR
417 M. luteus P. mirabilis E. coli C. albicans MRSA C. jeikeium C.
jejuni PF-139 S. epidermidis ALSKPAIQARTLCRRQDPP 418 M. luteus P.
mirabilis E. coli P. aeruginosa C. albicans S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-140 S. epidermidis
FHRRVIRASEWALTTRSFSTPLRSAAR 419 M. luteus P. mirabilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni M. smegmatis PF-141 S. epidermidis VVRRFQGM 420 M. luteus
C. albicans MRSA C. jeikeium PF-142 S. mutans GIDRGCQAAR 421 PF-143
S. epidermidis LSPRPIIVSRRSRADNNNDWSR 422 MRSA C. jeikeium PF-144
S. epidermidis RSGQPVGRPSRRAWLR 423 M. luteus E. coli C. albicans
MRSA S. pneumoniae E. faecalis C. jeikeium PF-145 S. epidermidis
GIVLTGRAGLVSGACSMALGVGLG 424 M. luteus P. mirabilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni M. smegmatis PF-146 S. epidermidis GCGKRRIITKSASRDTR 425
M. luteus P. aeruginosa C. albicans MRSA C. jeikeium PF-147 S.
epidermidis RRPRRRRSGHGQSASAA 426 M. luteus MRSA PF-148 S.
epidermidis RRGCTERLRRMARRNAWDLYAEHFY 427 M. luteus P. mirabilis E.
coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni M. smegmatis PF-149 S. epidermidis
GKVSVLTRVPRSLGGAPANQ 428 M. luteus E. coli MRSA C. jeikeium PF-150
S. epidermidis EIQAKGTG 429 MRSA PF-151 S. epidermidis
EEYPARVPLSGEDVTEARRH 430 MRSA E. faecalis C. jeikeium PF-152 S.
epidermidis VGYFIWKDSHSRKG 431 C. albicans MRSA E. faecalis C.
jeikeium PF-153 M. luteus GILARADCSQIA 432 P. mirabilis E. coli
MRSA PF-154 S. mutans GIKKSKHPSTDDYVVKTTIDSL 433 PF-155 C. jeikeium
GRYGDDSKERQGRAQ 434 PF-156 S. epidermidis LITAEQPATAPIAGK 435 C.
jeikeium PF-157 S. epidermidis HTAVVWLAGVSGCVALSHCEPA 436 M. luteus
P. mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
E. faecalis C. jeikeium C. jejuni PF-158 S. epidermidis
VRLESRPADLPE 437 PF-159 S. epidermidis TMAFVEKAQLRVPVGDDLPV 438
PF-160 S. epidermidis SFHASLTKNEKPIKSTG 439 PF-161 S. epidermidis
RGRALASTATTRPARRRR 440 M. luteus E. coli C. jejuni PF-162 S.
epidermidis GIRRLHSVENLNREISHRMAGLR 441 MRSA PF-163 S. epidermidis
TSWLRAAERQEIGEPTKTFGEKTTSL 442 PF-164 S. epidermidis
EEVSRALAGIGLGLGCRIG 443 M. luteus E. coli C. jeikeium PF-165 MRSA
GPVSVVASLRRGTTVQRHSQNNHNKG 444 C. jejuni KP PF-166 E. coli
SKAVSRKRSI 445 C. jeikeium PF-167 S. epidermidis
AIEGVIKKGACFKLLRHEMF 446 E. coli C. albicans MRSA C. jeikeium C.
jejuni PF-168 S. epidermidis VLPFPAIPLSRRRACVAAPRPRSRQRAS 447 M.
luteus E. coli C. albicans MRSA C. jeikeium C. jejuni PF-169 S.
epidermidis APGSAADSPRSRADD 448 E. coli C. albicans E. faecalis C.
jeikeium PF-170 S. epidermidis RLARGRPTNLCGRRG 449 M. luteus P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jejuni PF-171 S. epidermidis TQVTLCRTW 450 E. coli P.
aeruginosa S. pneumoniae PF-172 S. epidermidis
LTGVRRPWRAPWAGTSGWALR 451 M. luteus E. coli P. aeruginosa MRSA E.
faecalis C. jejuni PF-173 S. epidermidis AGRTAIVQGGG 452 M. luteus
P. mirabilis E. coli P. aeruginosa C. albicans C. jeikeium C.
jejuni PF-174 S. epidermidis RGGDSPARRRPGLAGPGGPG 453
P. aeruginosa C. jeikeium PF-175 S. epidermidis RRRPAGQRPEKASQAMIAA
454 E. faecalis PF-176 S. epidermidis RLTSNQFLTRITPFVFAQH 455 M.
luteus P. mirabilis E. coli C. albicans MRSA E. faecalis C.
jeikeium PF-177 M. luteus VTSEPGIAHDIRLLPRAAAFR 456 MRSA E.
faecalis C. jeikeium PF-178 S. epidermidis EVYSSPTNNVAITVQNN 457 M.
luteus B. subtilis P. mirabilis E. coli P. aeruginosa C. albicans
MRSA S. pneumoniae E. faecalis C. jeikeium PF-180 S. epidermidis
SGLGDLGFSSEAK 458 M. luteus P. aeruginosa C. albicans MRSA E.
faecalis C. jejuni M. smegmatis PF-181 S. epidermidis
GIAPRRNEWGAVGGR 459 M. luteus E. coli MRSA E. faecalis C. jeikeium
PF-182 S. epidermidis LPATRDKTRVPASVAGAP 460 M. luteus E. coli E.
faecalis C. jeikeium PF-183 S. epidermidis KPGISVENRQ 461 M. luteus
E. coli C. albicans MRSA E. faecalis C. jeikeium PF-184 S.
epidermidis LIADRHIRA 462 M. luteus E. coli P. aeruginosa C.
albicans MRSA C. jeikeium PF-185 E. coli RPAQARQGPGGLIADRHIRA 463
P. aeruginosa PF-186 S. epidermidis DADKNLSLERDRFAWRVAAP 464 M.
luteus E. coli P. aeruginosa MRSA C. jeikeium PF-187 S. epidermidis
EIQKIAKGVSGQVYGPSRQITISKKR 465 M. luteus E. coli MRSA PF-188 S.
epidermidis ARTFAGRLGTRYFGGLMRSTKA 466 M. luteus E. coli C.
albicans MRSA E. faecalis PF-189 S. epidermidis GNLTRSREAARATQ 467
M. luteus C. albicans MRSA E. faecalis C. jejuni PF-190 S.
epidermidis HFILRKPLLFMIHSLKTGPLDRF 468 M. luteus P. mirabilis E.
coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-191 E. coli QFCNFAWLFLASNNAQVSALA 469 P. aeruginosa C.
jejuni PF-192 S. epidermidis VEEDEAPPPHY 470 M. luteus P.
aeruginosa C. albicans E. faecalis C. jeikeium PF-193 S.
epidermidis PPHCPPGHAKKGWC 471 M. luteus E. coli MRSA E. faecalis
C. jejuni PF-194 C. jeikeium MKGNKLATAHEQPVKNSAPPL 472 PF-195 S.
epidermidis EMAEGSADDRLRKTPRDC 473 M. luteus E. faecalis C.
jeikeium PF-196 S. epidermidis TTARYIRRQCHTSITPLSQG 474 M. luteus
P. mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
E. faecalis C. jejuni PF-197 S. epidermidis CNALLRRGHPPSAL 475 M.
luteus C. albicans E. faecalis C. jejuni PF-200 S. epidermidis
GIELKSLIMAQIERWRQA 476 M. luteus MRSA E. faecalis C. jeikeium
PF-201 S. epidermidis GCRPASLSDADPDGR 477 M. luteus E. coli C.
albicans E. faecalis C. jeikeium C. jejuni PF-202 S. epidermidis
ALNRASLRLALGE 478 M. luteus E. coli MRSA E. faecalis C. jeikeium C.
jejuni PF-203 S. epidermidis SWKCHHLAI 479 M. luteus P. mirabilis
E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jejuni PF-204 S. epidermidis ALQKQDMNLPSVKNQLVFLKSTG 480 P.
mirabilis E. coli P. aeruginosa C. albicans C. jejuni PF-205 S.
epidermidis AGVLETPRCRGEYGAN 481 M. luteus E. coli P. aeruginosa C.
albicans MRSA E. faecalis C. jeikeium C. jejuni PF-206 M. luteus
KLRSASKKSLQEKSCGIMPEKPAG 482 C. albicans C. jeikeium C. jejuni
PF-207 M. luteus AAGCRDLGSLSSLVTNPS 483 C. jeikeium PF-208 S.
epidermidis DAYHCHLVRSPDAHDLSMRIGFV 484 C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-209 C. albicans
NYAVVSHT 485 C. jeikeium C. jejuni PF-210 S. epidermidis
EREDGCDAMPLP 486 P. aeruginosa C. albicans MRSA E. faecalis C.
jeikeium C. jejuni PF-211 S. epidermidis DSFDSLSPFRERGGEREDGCDAMPLP
487 M. luteus E. coli P. aeruginosa C. albicans S. pneumoniae E.
faecalis C. jeikeium C. jejuni M. smegmatis PF-212 M. luteus
NDSKASN 488 P. aeruginosa PF-213 S. epidermidis MTTGVDFIIEKV 489
PF-214 S. mutans GHLRVCWVFSASLLTPFRSATLI 490 S. epidermidis M.
luteus E. coli P. aeruginosa
A. baumannii PF-215 S. epidermidis ELKITNYNVNTVLYRYYKWGNDLCE 491 M.
luteus P. aeruginosa A. baumannii PF-216 S. mutans
ESVDKITEALEEDGFPAKVQ 492 E. coli PF-217 S. mutans DWEFTHKTIPQKK 493
PF-218 S. epidermidis SETPEKPVGTFFYSIYYKIIL 494 M. luteus P.
aeruginosa A. baumannii PF-219 S. epidermidis
FLALAVIAGLFKVILIYAAPYLK 495 M. luteus P. aeruginosa A. baumannii
PF-221 S. epidermidis VFDNIDINF 496 M. luteus P. aeruginosa PF-222
S. epidermidis HIKETR 497 PF-223 S. epidermidis VKFCIECQTKLERKRR
498 M. luteus A. baumannii PF-224 S. epidermidis DYFYITLSQKNTF 499
P. aeruginosa A. baumannii PF-225 S. epidermidis MNCASPEFKKLMELYK
500 PF-226 A. baumannii LMFFSENMDKRDTLSGKFRYFAGSKVI 501 KLMNWLSENGK
PF-228 S. mutans NQLGSQAFAQL 502 PF-229 S. epidermidis
DPILIQIGFTRFALRKAEAEKIEIQVEEGV 503 M. luteus PA P. aeruginosa A.
baumannii PF-230 S. mutans EDKPTNTIQEIKPVKWQ 504 PF-231 S. mutans
AVRDFKKSVREEDEAASLNSPRTIDAQ 505 VKTSESTSVKS PF-232 S. epidermidis
FDQLYALEREGKLDELLA 506 M. luteus PF-233 S. epidermidis
DANAMARTTIAIVYILALIALTISYSL 507 M. luteus P. aeruginosa A.
baumannii PF-234 S. epidermidis RTPYILRS 508 M. luteus PF-235 S.
epidermidis GIPFSKPHKRQVNYMKSDVLAYIEQNK 509 M. luteus MAHTA PF-236
S. mutans KEIRTATVAELNAKRRLTSAEQALAEVS 510 S. epidermidis E. coli
C. albicans S. pneumoniae E. faecalis PF-237 S. epidermidis
YVKPKVGVHE 511 PF-238 S. mutans RNAVVVTEATFPKYEEEITNYLNRRFGE 512 S.
epidermidis DWSLKLEKCSVA E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-239 S. mutans PKHNVVTGVSVDLDYKP 513 E.
coli PF-240 S. mutans RITEVPPDEHSDR 514 E. coli PF-242 S. mutans
KLFEDPLIKSKAVENFQTTWHEQCLAK 515 E. coli ELAKNM PF-244 S.
epidermidis HMRTISYLLAFAKFSLFIPPKQSLKRL 516 M. luteus P. aeruginosa
A. baumannii PF-245 S. epidermidis MNDVKPVVQPKQTLKAFLVQLLSVRA 517
M. luteus GVYIKQNNQLPKTKG P. aeruginosa A. baumannii PF-246 S.
mutans QPDEKAEFFDPSLDKVYRHPTFYHIPDG 518 IEHM PF-247 S. epidermidis
ETAASETH 519 PF-248 S. mutans ILSKLWFWMINSLGVVLLVSYWLLAK 520 S.
epidermidis WGVA M. luteus E. coli P. aeruginosa A. baumannii
PF-249 S. epidermidis INSRYKISF 521 M. luteus PF-252 S. mutans
MKKLVAALAVIVILTGCVYDPVNYDKI 522 HDQEFQDHLRQNG PF-253 S. epidermidis
VRDDDS 523 M. luteus PF-254 S. epidermidis
FIYGVGFVPHFWLWKWLFSPWIAWPL 524 M. luteus MLLGYYIWFLT P. aeruginosa
A. baumannii PF-255 P. aeruginosa DHKINESQHNPFRSDSNKQNVDFF 525
PF-256 S. epidermidis EYFKQVYVKNEKIYSFWICKDLSPKEA 526 AKRAEDILVKLK
PF-257 S. epidermidis VWENRKKYLENEIERHNVFLKLGQEVI 527 KGLNALASRGR
PF-259 S. epidermidis LPFSKIGRRVSYKKKDVLKYEQSKTVL 528 P. aeruginosa
NTAQLATV A. baumannii PF-262 S. mutans DPHSEIDVTRYCQLHHFTCQTMQISERE
529 S. epidermidis FHYLIETQ M. luteus E. coli P. aeruginosa A.
baumannii PF-263 S. epidermidis NLKKCPC 530 M. luteus A. baumannii
PF-265 S. epidermidis MKTLFFPLFLIIFVLIIQALDQSYQKKIGI 531 M. luteus
SKPQKHPEFMQ A. baumannii PF-266 S. mutans DQEKKNKTEESTEQ 532 PF-267
M. luteus SDDKRTD 533 PF-268 S. mutans EVLLSDLRPDIFSET 534 PF-270
S. epidermidis MYLTPYAWIAVGSIFAFSVTTIKIGDQN 535 M. luteus
DEKQKSHKNDVHKR P. aeruginosa PF-271 S. epidermidis AAQPQTTSP 536 M.
luteus P. aeruginosa A. baumannii PF-273 S. epidermidis
LVGALLIFVALIYMVLKGNADKN 537 M. luteus P. aeruginosa A. baumannii
PF-275 S. mutans LVSGVANTVKNTAHTVGNTAKHAGHV 538 AADTTVKATKKQQVK
PF-276 S. epidermidis LDLALSTNSLNLEGFSF 539 PF-278 M. luteus
LSLATFAKIFMTRSNWSLKRFNRL 540 A. baumannii PF-279 S. mutans
SHIGFISISACLAVLLGIARLFVWTWVKF 541 S. epidermidis FA M. luteus E.
coli P. aeruginosa A. baumannii PF-281 S. mutans
SYNTYYNKLIHGQRTPDGM 542 E. coli PF-282 S. mutans QNNDTSAWCGSAHKNGNS
543 PF-283 B. subtilis MIRIRSPTKKKLNRNSISDWKSNTSGRF 544 B. fragilis
FY C. difficile PF-284 C. difficile MRYITYSLIPRLLSKKVIHQQ 545
PF-285 S. mutans VPAKLLRVIDEIPE 546 PF-288 S. mutans IYQLLNIEYSEDD
547 E. coli PF-289 C. difficile MGRHLWNPSYFVATVSENTEEQIRKYR 548 KNK
PF-291 S. mutans DVDGAIESEL 549 E. coli PF-292 S. epidermidis
SFVSTTVRLIFEESKRYKF 550 B. subtilis B. fragilis PF-294 S.
epidermidis DFLVNFLWFKGELNWGKKRYK 551 C. difficile PF-295 C.
difficile NIQVYESECGNYIFKKSDESFLIDIFDKN 552 GTH PF-297 S.
epidermidis ISKGIDDIVYVINKILSIGNIFKIIKRK 553 B. subtilis B.
fragilis PF-299 B. subtilis LATKLKYEKEHKKM 554 PF-300 B. subtilis
VKDVLLELFNKIIGA 555 C. difficile PF-301 C. difficile
GIVLIGLKLIPLLANVLN 556 PF-304 S. mutans
LVKDTSDIKNDLNNIEIVTSKNSNDIAKL 557 KSVK PF-305 C. difficile
MREWICPSCNETHDRDINASINILKEGL 558 RLITIQNK PF-306 C. difficile
GCILPHKKDNYNYIMSKFQDLVKITSKK 559 PF-307 S. epidermidis
MKRRRCNWCGKLFYLEEKSKEAYCCK 560 B. subtilis ECRKKAKKVKK B. fragilis
C. difficile PF-308 C. difficile QQYLILDRM 561 PF-309 S. mutans
GIPGMTAAPAEENEQEENADEE 562
E. coli PF-311 C. difficile IDAVTKKKTTCMIRAPTKIPIAHTDN 563 PF-313
S. epidermidis YITSHKNARAIIKKFERDEILEEVITHYL 564 C. difficile NRK
PF-314 S. mutans ECLKKAIKSKALNKAFKIDVPDEVYDN 565 LLMELEEYEK PF-317
S. mutans LILVSDI 566 PF-319 S. epidermidis
SIGSMIGMYSFRHKTKHIKFTFGIPFILFL 567 B. subtilis QFLLVYFYILK C.
difficile PF-320 S. mutans DSGYYALLENKEERVVWDGEVVANNI 568 E. coli
FNNLWIVVNKVKTG PF-323 S. mutans ARESIEKSHVPVDATIVGVVDSFEVFDE 569
PF-324 C. difficile HFSLL 570 PF-325 S. mutans LTIDEKLRNHR 571 E.
coli PF-326 S. mutans VIVGNLGAQKEKRNDTPISAKKDIMGD 572 E. coli
KTVRVRADLHH PF-328 S. mutans NGNEKAFSEVENLVK 573 PF-329 S.
epidermidis IGILFDKSVRKY 574 PF-333 S. mutans YMTKKLVEMAEQQMAGKSNR
575 PF-334 S. epidermidis QQYLILDRM 576 C. difficile PF-336 S.
mutans MLTSRKKRLKKIVEEQNKKDESI 577 E. coli PF-337 S. epidermidis
YMTKKLVEMAERQMAGK 578 PF-338 S. mutans KGTSCPDQLSKAIRQSI 579 PF-340
S. mutans VKDVLLELFNKIIGA 580 E. coli PF-344 B. subtilis
DERLPEAKAIRNFNGSVMVLGR 581 C. jejuni PF-347 S. epidermidis
GIFTGVTVVVSLKHC 582 B. subtilis B. fragilis E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis PF-348 B. subtilis
ESASAAEWYNPNMNVKKAICMG 583 E. coli P. aeruginosa C. albicans E.
faecalis C. jejuni PF-349 S. epidermidis
MPKSCHVPVLCDFFFLVIIKFLALFKTIQS 584 B. subtilis B. fragilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-350 S. epidermidis LAVILRAIVY 585 E. coli E. faecalis
C. jeikeium C. jejuni PF-351 S. mutans YLFFKGKKVAEEEATKDEVKR 586
PF-352 C. jeikeium RVKKIG 587 PF-353 S. epidermidis
EKTNFKGVKRNFYKKASFFV 588 M. luteus B. subtilis E. coli C. albicans
S. pneumoniae E. faecalis C. jeikeium C. jejuni PF-354 S.
epidermidis FTFSKCRASNGRGFGTLWL 589 B. subtilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni PF-355 S. epidermidis WIAIGLLLYFSLKNQ 590 B. subtilis B.
fragilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium PF-356 S. epidermidis VSIKIGAIVIGMIGLMELLTE
591 B. subtilis B. fragilis E. coli P. aeruginosa C. albicans MRSA
S. pneumoniae E. faecalis C. jeikeium PF-357 S. epidermidis
MLTIIIGFIFWTMTLMLGYLIGEREGRK 592 M. luteus HE P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-358 S. epidermidis RNTAHNIKWRSKN 593 B. subtilis E.
coli C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-359 S. epidermidis MTVMEDPGSEQRNKIQSPMKGEDFSAL 594 B.
fragilis FGR P. aeruginosa C. albicans MRSA E. faecalis C. jeikeium
PF-360 S. epidermidis MEQKVKVIFVPRSKPDNQLKTFVSAVL 595 B. subtilis
FKA E. coli P. aeruginosa C. albicans E. faecalis C. jeikeium C.
jejuni PF-361 S. epidermidis NQVTEGIRLLVE 596 E. coli E. faecalis
C. jejuni PF-362 S. epidermidis NIERILKEKVWMIRCVE 597 E. coli P.
aeruginosa C. albicans E. faecalis C. jejuni PF-363 B. subtilis
SMLSVTVMCLMHASVAANQAMEKKV 598 E. coli P. aeruginosa C. albicans S.
pneumoniae E. faecalis PF-364 S. epidermidis LVNGIKI 599 B.
fragilis P. aeruginosa C. jeikeium C. jejuni PF-365 S. epidermidis
LYKQKIQLEEELEKLKDDRQ 600 B. subtilis B. fragilis P. aeruginosa C.
albicans PF-366 S. epidermidis ALCSVIKAIELGIINVHLQ 601 M. luteus B.
fragilis P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-367 B. subtilis
TKTPGTFTPGTGIQKTAVPL 602 PF-368 C. jeikeium MLKQTA 603 C. jejuni
PF-369 B. subtilis MSEAVNLLRGARYSQRYAKNQVPYEVI 604 B. fragilis IEK
E. coli P. aeruginosa C. albicans S. pneumoniae C. jeikeium C.
jejuni PF-370 S. epidermidis VIFLHKESGNLKEIFY 605 E. coli P.
aeruginosa E. faecalis C. jejuni PF-371 S. epidermidis TFIYNEF 606
B. fragilis C. jejuni PF-372 C. jeikeium KKQDKRIEDKYKRMKKGD 607 C.
jejuni PF-373 S. epidermidis HFYLLFER 608 E. coli P. aeruginosa C.
albicans MRSA E. faecalis C. jejuni PF-374 S. epidermidis
HLFFVKGMFILCQKNQINDE 609 B. subtilis
B. fragilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-375 S. epidermidis
MDSAKAQTMRTDWLAVSCLVASAYLR 610 B. subtilis SMLA B. fragilis E. coli
P. aeruginosa C. albicans S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-376 S. epidermidis MTVFEALMLAIAFATLIVKISNKNDKK 611 B.
subtilis B. fragilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-378 B. subtilis
ESAKSNLNFLMQEEWALFLLL 612 B. fragilis E. coli P. aeruginosa C.
jeikeium PF-379 S. epidermidis VFVVLFIIYLASKLLTKLFPIKK 613 B.
subtilis B. fragilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-380 S. epidermidis
KKIIPLITLFVVTLVG 614 B. subtilis B. fragilis E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-381 E. coli QGANPCQQVGFTVNDPDCRLAKTV 615 P. aeruginosa C. jejuni
PF-382 S. epidermidis KYKCSWCKRVYTLRKDHKTAR 616 B. subtilis B.
fragilis E. coli P. aeruginosa E. faecalis C. jeikeium C. jejuni
PF-383 S. epidermidis WSEIEINTKQSN 617 B. subtilis B. fragilis E.
coli C. jejuni PF-384 E. faecalis HISKERFEAY 618 C. jeikeium C.
jejuni PF-385 S. epidermidis MIKKSILKIKYYVPVLISLTLILSA 619 E. coli
P. aeruginosa C. albicans E. faecalis PF-386 S. epidermidis
FTLTLITTIVAILNYKDKKK 620 B. subtilis B. fragilis E. coli P.
aeruginosa C. albicans S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-387 B. subtilis GAVGIAFFAGNMKQDKRIADRQNKKSE 621 E. coli
KK P. aeruginosa E. faecalis C. jeikeium C. jejuni PF-388 E.
faecalis ITPLLDEIGKVCIDKISK 622 C. jeikeium C. jejuni PF-389 S.
epidermidis GLQFKEIAEEFHITTTALQQWHKDNGY 623 C. albicans PIYNKNNRK
MRSA S. pneumoniae E. faecalis C. jeikeium PF-390 S. epidermidis
VVAYVITQVGAIRF 624 P. aeruginosa C. albicans MRSA PF-392 S.
epidermidis DPAGCNDIVRKYCK 625 B. subtilis S. pneumoniae C.
jeikeium C. jejuni PF-393 S. epidermidis DLVQSILSEFKKSG 626 E. coli
C. albicans MRSA S. pneumoniae C. jejuni PF-394 S. epidermidis
VLKEECYQKN 627 MRSA C. jejuni PF-395 S. epidermidis
YCVPLGNMGNMNNKIW 628 E. coli P. aeruginosa S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-396 S. epidermidis
LIYTILASLGVLTVLQAILGREPKAVKA 629 E. coli P. aeruginosa C. albicans
E. faecalis C. jeikeium PF-397 S. epidermidis VEDLMEDLNA 630 MRSA
S. pneumoniae E. faecalis C. jejuni PF-398 S. epidermidis
ILVVLAGILLVVLSYVGISKFKMNC 631 B. subtilis B. fragilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni PF-399 S. epidermidis FPIISALLGAIICIAIYSFIVNRKA 632 M.
luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jejuni PF-400 S. epidermidis
VIAWKFRNKFENSGV 633 E. coli S. pneumoniae E. faecalis C. jeikeium
PF-401 S. epidermidis YWLSRVTTGHSFAFEKPVPLSLTIK 634 E. coli P.
aeruginosa MRSA E. faecalis C. jejuni PF-402 S. epidermidis
FIDVLKSKINEFLN 635 P. aeruginosa E. faecalis C. jejuni PF-403 E.
coli LLSTEQLLKYYDGETFDGFQLPSNE 636 P. aeruginosa S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-404 S. epidermidis VLYFQATVV 637
E. coli P. aeruginosa E. faecalis C. jeikeium C. jejuni PF-405 S.
epidermidis LVRIEVDDLEEWYERNFI 638 E. coli E. faecalis PF-406 E.
coli YLEMNADYLSNMDIFDELWEKYLENNK 639 C. jejuni PF-407 S.
epidermidis KPKNKKEKTVISYEKLLSMY 640 B. subtilis E. coli P.
aeruginosa MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-408 S. epidermidis YCVPLGNMGNMNNKIW 641 E. coli P. aeruginosa
MRSA E. faecalis C. jeikeium C. jejuni PF-409 S. epidermidis
DLVQSILSEFKKSG 642 MRSA C. jeikeium C. jejuni PF-410 S. epidermidis
FALELIALCRNLFIVYFP 643 M. luteus
B. fragilis P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-411 M. luteus WVAVAILLNIALQTQLT 644 B.
subtilis B. fragilis P. mirabilis P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-412 M. luteus
TSGWLGQLEQ 645 E. coli C. albicans C. jeikeium C. jejuni PF-413 P.
aeruginosa TFAGSIKIGVPDLVHVTFNCKR 646 C. albicans C. jejuni PF-414
E. coli LLNKKLE 647 C. albicans C. jeikeium PF-416 S. pneumoniae
SKAGLYGKIERSDKRE 648 C. jeikeium PF-417 S. epidermidis DSYFRS 649
C. jeikeium C. jejuni PF-418 S. epidermidis FFLVHFYIRKRKGKVSIFLNYF
650 M. luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA
S. pneumoniae E. faecalis C. jeikeium C. jejuni PF-421 C. jeikeium
KHCFEITDKTDVV 651 PF-422 C. albicans MSRKKYENDEKSQKKLKIGRKSDVFYG
652 MRSA IID C. jeikeium PF-423 S. epidermidis
AGKKERLLSFREQFLNKNKKK 653 M. luteus E. coli S. pneumoniae E.
faecalis C. jeikeium PF-424 S. epidermidis IAAFVTSRAFSDTVSPI 654 C.
albicans MRSA PF-425 S. epidermidis MMELVLKTIIGPIVVGVVLRIVDKWLN 655
M. luteus KDK E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
C. jeikeium PF-426 S. epidermidis MLQKYTQMISVTKCIITKNKKTQENVD 656
E. coli AYN P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium PF-427 M. luteus YVLEYHGLRATQDVDAFMAL 657 P.
aeruginosa C. albicans C. jejuni PF-428 S. epidermidis ENEESIF 658
C. albicans E. faecalis C. jeikeium PF-429 S. epidermidis
AATLICVGSGIMSSL 659 S. pneumoniae C. jeikeium PF-430 S. epidermidis
AVVCGYLAYTATS 660 M. luteus E. coli S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-431 S. epidermidis VAYAAICWW 661 M. luteus E.
coli P. aeruginosa MRSA S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-432 S. epidermidis FNGDSEFFLCIAF 662 M. luteus E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni PF-433 S. epidermidis MRKEFHNVLSSGQLLADKRPARDYNRK 663 E.
coli S. pneumoniae C. jeikeium PF-434 S. epidermidis
GQLLADKRPARDYNRK 664 M. luteus S. pneumoniae C. jeikeium PF-435 C.
jeikeium MSRWDGHSDKGEAPAGKPPMHGFGLN 665 GENK PF-436 C. jeikeium
KKHVLVGKQEKNG 666 PF-438 S. epidermidis QPYFQNQFKKITGYTPLQYRKEKR
667 E. coli S. pneumoniae C. jeikeium C. jejuni PF-439 S.
epidermidis RVLVLKKFHGIMDGNRNVAVFFVGQ 668 M. luteus B. fragilis P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-440 S. epidermidis
MFIISPDLFNIAVILYILFFIHDILLLILS 669 M. luteus P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-441 C. jeikeium TQVHKMARGIDPGPANGIYR 670
PF-442 S. epidermidis MQIFYIKTKIFLSFFLFLLIFSQCFYKIEE 671 E. coli C.
albicans S. pneumoniae E. faecalis PF-443 S. epidermidis
KLLYFFNYFENLQQVHLLVQL 672 M. luteus P. mirabilis E. coli P.
aeruginosa C. albicans S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-444 M. luteus MAAKLWEEGKMVYASSASMTKRLKL 673 C. albicans
AMSKV S. pneumoniae C. jeikeium PF-445 M. luteus ASMTKRLKLAMSKV 674
S. pneumoniae C. jeikeium PF-446 M. luteus SGNEKV 675 C. jeikeium
PF-447 S. epidermidis IDKSRNKDQFSHIFGLYNICSG 676 M. luteus E. coli
S. pneumoniae PF-448 S. epidermidis SLQSQLGPCLHDQRH 677 M. luteus
P. mirabilis E. coli S. pneumoniae E. faecalis C. jeikeium C.
jejuni PF-450 S. epidermidis HRNLIILQRTIFI 678 M. luteus E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
C. jejuni PF-451 S. epidermidis MVNYIIGSYMLYREQNNNEALRKFDIT 679 M.
luteus LAM E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni M. smegmatis PF-452 M. luteus
MNNWIKVAQISVTVINEVIDIMKEKQN 680 P. aeruginosa GGK C. albicans S.
pneumoniae E. faecalis
C. jeikeium M. smegmatis PF-453 M. luteus IIQDIAHAFGY 681 E. coli
P. aeruginosa S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-454 S. epidermidis MSVFVPVTNIFMFIMSPIFNVNLLHFKV 682 M. luteus YI
E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni M. smegmatis PF-456 C. albicans TCVKPRTIN 683
MRSA E. faecalis C. jeikeium C. jejuni PF-457 C. albicans INKYHHIA
684 S. pneumoniae E. faecalis C. jeikeium PF-458 S. epidermidis
ISLIIFIMLFVVALFKCITNYKHQS 685 M. luteus E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-459 P. aeruginosa EKRMSFNENQSHRPLL 686 PF-460 S. epidermidis
MEHVLPFQNTPPNIVIIYKDFTHLKSITFS 687 M. luteus P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni M. smegmatis PF-461 E. coli
MTLAIKNCSVTKCLGFGDFVNDDSDSY 688 S. pneumoniae FDA PF-462 E.
faecalis KNKTDTL 689 C. jeikeium PF-463 S. epidermidis
MVILVFSLIFIFTDNYLVYQSKSIKEDVMI 690 E. coli P. aeruginosa C.
albicans S. pneumoniae E. faecalis M. smegmatis PF-464 S.
epidermidis VDMVNRFLGN 691 C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-465 S. epidermidis
KPVGKALEEIADGKIEPVVPKEYLG 692 M. luteus E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-466 MRSA VRKSDQ 693 C. jeikeium C. jejuni PF-467 MRSA YYKDYFKEI
694 E. faecalis C. jeikeium C. jejuni PF-469 S. epidermidis
YKVNYNNIDNHFNTLRH 695 M. luteus P. mirabilis E. coli C. albicans
MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni PF-470 M.
luteus PYSDSYATRPHWEQHRAR 696 E. coli MRSA E. faecalis C. jeikeium
C. jejuni PF-471 S. epidermidis MVGKIRGVTPRNDLLNANITGQLNLNY 697 M.
luteus RLI E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-472 S. epidermidis
MHISHLLDEVEQTEREKAVNVLENMNG 698 E. coli NVI P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-473 S.
epidermidis MAADIISTIGDLVKWIIDTVNKFKK 699 E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis PF-474 S. epidermidis
MHRNLVLVKMEPIPHIMIIANQIGIIIEKA 700 M. luteus P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni M. smegmatis PF-475 S. epidermidis
MREKVRFTQAFKLFWTNYFNFKGRSRR 701 M. luteus SEY P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-476 M. luteus WADAQYKLCENCSE 702 P. mirabilis
C. albicans S. pneumoniae E. faecalis C. jeikeium C. jejuni PF-477
S. epidermidis HKNKLNIPHIKS 703 M. luteus C. albicans S. pneumoniae
C. jeikeium C. jejuni PF-478 S. epidermidis HLFILKSHLKPFPPFRYTYD
704 M. luteus P. mirabilis E. coli C. albicans S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-479 S. epidermidis AYILKRREEKNK
705 M. luteus P. mirabilis E. coli C. albicans S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-480 S. epidermidis
MVEILVNTAISVYIVALYTQWLSTRDNL 706 M. luteus KA P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni M. smegmatis PF-481 C. jeikeium
DELYEIMDKVIEEFNKDIEQNNNNGNN 707 EDLTENKIN PF-482 S. epidermidis
LVGYVRTSGTVRSYKIN 708 M. luteus P. mirabilis E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-483 P. mirabilis EDNKDKKDKKDK 709 C. jeikeium C. jejuni PF-484
S. epidermidis HKKDIRKQVFKN 710 M. luteus P. mirabilis E. coli E.
faecalis C. jeikeium C. jejuni PF-486 S. mutans MQKEGEEDY 711
PF-487 S. mutans MYKAIAVLAMTIMAFFIFVYPFFIVGLILG 712
E. coli PF-488 S. mutans YPNEQGHHKNNLKNIIIE 713 E. coli PF-489 S.
mutans KVDRVSTTITEKIK 714 PF-490 S. mutans RLILVSGNATVQK 715 E.
coli PF-491 S. mutans IHQYSSKPDIVGQEAKTVQQINS 716 E. coli PF-492 S.
mutans IQIDAASFYSISKSTIK 717 B. subtilis E. coli PF-493 S. mutans
PGAFFFCRGRGCWCGIGW 718 B. subtilis E. coli PF-494 S. mutans
FTEPLRPLQAKGQIISIKPSTSSS 719 PF-495 S. mutans KGIYKKRTY 720 E. coli
PF-496 S. mutans EVTKRLVALAQQQLRG 721 E. coli PF-497 S. mutans
LVLRICTDLFTFIKWTIKQRKS 722 B. subtilis E. coli PF-498 S. mutans
MSEEEEVSEKVYNYLRRNEFFEVRKEE 723 E. coli FSA PF-499 S. mutans
VYSFLYVLVIVRKLLSMKKRIERL 724 E. coli PF-500 S. mutans
MGIFKEEKIKFIDCKGEEVILKIKIKDIKK 725 E. coli PF-501 S. mutans
GSTAHKSPIGSTNNQWGMKKTPTD 726 PF-502 S. mutans NKGKQMQDQTGKQPIVDNG
727 PF-503 S. mutans VVTLKDIVAVIEDQGYDVQ 728 PF-504 S. mutans
ILSVELSTKTSASGS 729 E. coli PF-505 S. mutans GYTKDPGTGI 730 PF-506
S. mutans SGRGFALIVVLFILLIIVGAACIR 731 E. coli PF-507 S. mutans
LALSIANLFKKKA 732 E. coli PF-508 S. mutans VSTFGKVVKVVDEK 733
PF-509 S. mutans EAKVQAKGEQIACNNY 734 B. subtilis E. coli PF-510 S.
mutans WYLYKKQSNQNDRGIPK 735 E. coli PF-511 E. coli
VMQSLYVKPPLILVTKLAQQN 736 P. aeruginosa S. pneumoniae C. jeikeium
PF-512 S. pneumoniae SFMPEIQKNTIPTQMK 737 C. jeikeium PF-513 C.
albicans SNGVGLGVGIGSGIRF-NH2 738 PF-514 S. epidermidis
QRFYKLFYHIDLTNEQALKLFQVK 739 E. coli P. aeruginosa C. albicans MRSA
S. pneumoniae E. faecalis C. jeikeium PF-515 S. epidermidis
DKSTQDKDIKQAKLLAQELGL-NH2 740 C. albicans S. pneumoniae C. jeikeium
PF-517 C. jejuni VKPTMTASLISTVC 741 PF-518 S. epidermidis
SFYSKYSRYIDNLAGAIFLFF 742 E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-519 M. luteus YLVYSGVLATAAAF-NH2 743 E.
faecalis C. jeikeium PF-520 S. epidermidis
LGLTAGVAYAAQPTNQPTNQPTNQPTN 744 M. luteus QPTNQPTNQPRW-NH2 E. coli
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-521 S. epidermidis CGKLLEQKNFFLKTR 745 E. coli P. aeruginosa S.
pneumoniae E. faecalis PF-522 S. epidermidis
FELVDWLETNLGKILKSKSA-NH2 746 E. coli P. aeruginosa S. pneumoniae E.
faecalis PF-523 S. epidermidis ASKQASKQASKQASKQASKQASRSLKN 747 M.
luteus HLL C. albicans S. pneumoniae C. jeikeium C. jejuni PF-524
S. epidermidis PDAPRTCYHKPILAALSRIVVTDR 748 E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-526 S.
epidermidis VLLLFIFQPFQKQLL-NH2 749 E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-527 S. epidermidis GSVIKKRRKRMAKKKHRKLLKKTRIQR 750 M. luteus
RRAGK P. mirabilis E. coli P. aeruginosa MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-528 S. epidermidis
LVDVVVLIRRHLPKSCS-NH2 751 P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis PF-529 S. epidermidis LSEMERRRLRKRA-NH2 752
E. coli C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
PF-537 S. epidermidis LANDYYKKTKKSW 753 M. luteus P. mirabilis E.
coli C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-539
S. epidermidis SIILTKKKRRKIPLSIDSQIYKYTFKQ 754 M. luteus B.
subtilis P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium PF-540 C. albicans
KSILILIKVIFIGQTTIIL 755 PF-542 C. jeikeium KKDNPSLNDQDKNAVLNLLALAK
756 PF-543 S. epidermidis NILFGIIGFVVAMTAAVIVTAISIAK 757 M. luteus
B. subtilis P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium PF-544 S. epidermidis
FGEKQMRSWWKVHWFHP 758 M. luteus P. mirabilis P. aeruginosa MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-545 S. epidermidis
RESKLIAMADMIRRRI-NH2 759 E. coli P. aeruginosa S. pneumoniae E.
faecalis C. jeikeium PF-546 S. epidermidis PIIAPTIKTQIQ 760 E. coli
C. albicans S. pneumoniae E. faecalis C. jeikeium PF-547 S.
epidermidis WSRVPGHSDTGWKVWHRW-NH2 761 E. coli P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis PF-548 M. luteus
ARPIADLIHFNSTTVTASGDVYYGPG 762
P. mirabilis E. coli P. aeruginosa C. albicans S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-549 E. coli TGIGPIARPIEHGLDS 763
C. albicans S. pneumoniae C. jeikeium PF-550 S. pneumoniae
STENGWQEFESYADVGVDPRRYVPL 764 PF-551 S. pneumoniae
QVKEKRREIELQFRDAEKKLEASVQAE 765 PF-552 S. pneumoniae
ELDKADAALGPAKNLAPLDVINRS 766 PF-553 S. epidermidis
LTIVGNALQQKNQKLLLNQKKITSLG 767 E. coli P. aeruginosa C. albicans
MRSA S. pneumoniae C. jeikeium PF-554 S. pneumoniae
AKNFLTRTAEEIGEQAVREGNINGP 768 PF-555 MRSA
EAYMRFLDREMEGLTAAYNVKLFTEAIS 769 S. pneumoniae C. jeikeium PF-556
S. epidermidis SLQIRMNTLTAAKASIEAA 770 M. luteus B. fragilis P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis PF-557 S. pneumoniae AANKAREQAAAEAKRKAEEQAR 771 PF-558 S.
epidermidis ADAPPPLIVRYS 772 E. coli C. albicans C. jeikeium C.
jejuni PF-559 S. epidermidis SRPGKPGGVSIDVSRDRQDILSNYP 773 M.
luteus C. albicans C. jeikeium C. jejuni PF-560 S. epidermidis
FGNPFRGFTLAMEADFKKRK 774 M. luteus E. coli S. pneumoniae C.
jeikeium C. jejuni PF-562 S. epidermidis TPEQWLERSTVVVTGLLNRK 775
M. luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-563 S. epidermidis
RPELDNELDVVQNSASLDKLQASYN 776 M. luteus C. jeikeium PF-564 S.
epidermidis TIILNDQINSLQERLNKLNAETDRR 777 C. albicans S. pneumoniae
C. jeikeium PF-566 P. mirabilis EAQQVTQQLGADFNAITTPTATKV 778 S.
pneumoniae PF-567 S. epidermidis QQRVKAVDASLSQVSTQVSGAVASA 779 P.
aeruginosa C. albicans MRSA S. pneumoniae C. jeikeium PF-568 S.
epidermidis TQAVQVKTAQAQQQ 780 PF-569 M. luteus
KSKISEYTEKEFLEFVEDIYTNNK 781 P. mirabilis S. pneumoniae E. faecalis
C. jeikeium PF-570 S. pneumoniae KKFPTEESHIQAVLEFKKLTEHPSG 782 C.
jeikeium PF-572 S. epidermidis WRASKGLPGFKAG 783 M. luteus E. coli
S. pneumoniae C. jeikeium PF-573 S. epidermidis
EKKLIVKLIDSIGKSHEEIVGAG 784 S. pneumoniae PF-575 M. luteus
LNFRAENKILEKIHISLIDTVEGSA 785 E. coli C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium PF-576 M. luteus
AYSGELPEPLVRKMSKEQVRSVMGK 786 P. mirabilis E. coli P. aeruginosa C.
albicans S. pneumoniae PF-577 S. epidermidis
PFETRESFRVPVIGILGGWDYFMHP 787 M. luteus P. mirabilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis PF-578 S.
epidermidis QKANLRIGFTYTSDSNVCNLTFALLGSK 788 M. luteus P. mirabilis
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-579 S. epidermidis MILVCAAVIWGRVLFILKFPIYFSIRLAFL 789
M. luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-580 S. epidermidis
EILNNNQVIKELTMKYKTQFESNLGGW 790 M. luteus TARARR E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
PF-581 S. epidermidis WTARARR 791 M. luteus E. coli P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-583 S.
epidermidis KFQGEFTNIGQSYIVSASHMSTSLNTGK 792 M. luteus E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
PF-584 S. epidermidis SYIKNLSNQKFLIAF 793 M. luteus P. mirabilis C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-585 S.
epidermidis DYNHLLNVVQDWVNTN 794 E. coli C. albicans MRSA S.
pneumoniae C. jeikeium PF-586 S. epidermidis FFNQANYFFKEF 795 M.
luteus E. coli P. aeruginosa MRSA S. pneumoniae E. faecalis C.
jeikeium C. jejuni PF-587 S. epidermidis
ASGKYQSYLLNVYVDSKKDRLDIFDKL 796 M. luteus KAKAKFVL E. coli MRSA S.
pneumoniae E. faecalis C. jeikeium PF-588 S. epidermidis
ESVEAIKAKAIK 797 E. coli C. albicans E. faecalis C. jeikeium C.
jejuni PF-589 S. epidermidis APLRIDEIRNSNVIDEVLDCAPKKQEHFF 798 C.
albicans VVPKIIE MRSA S. pneumoniae PF-590 S. epidermidis
YYQAKLFPLL 799 M. luteus E. coli E. faecalis C. jeikeium PF-592 S.
epidermidis IMKNYKYFKLFIVKYALF 800 M. luteus P. mirabilis E. coli
P. aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium C. jejuni
PF-593 C. jeikeium MEISTLKKEKLHVKDELSQYLANYKK 801 PF-594 C.
jeikeium IVSAIV 802 PF-595 S. epidermidis LQNKIYELLYIKERSKLCS 803
M. luteus P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni PF-596 S. epidermidis
SKMWDKILTILILILELIRELIKL 804 M. luteus P. mirabilis E. coli P.
aeruginosa MRSA E. faecalis C. jeikeium C. jejuni PF-597 P.
mirabilis DEIKVSDEEIEKFIKENNL 805 PF-598 S. epidermidis
MKFMLEVRNKAISAYKEITRTQI 806 M. luteus P. mirabilis P. aeruginosa C.
albicans MRSA S. pneumoniae C. jeikeium PF-599 S. epidermidis
LFEIFKPKH 807 P. mirabilis E. coli C. albicans MRSA S. pneumoniae
C. jeikeium PF-600 S. epidermidis TKKIELKRFVDAFVKKSYENYILERELK 808
M. luteus KLIKAINEELPTK B. subtilis P. mirabilis E. coli P.
aeruginosa MRSA S. pneumoniae E. faecalis C. jeikeium PF-601 C.
jeikeium YRVTVKALE 809 PF-602 P. mirabilis LEKEKKEYIEKLFKTK 810 C.
jeikeium PF-603 S. epidermidis IDKLKKMNLQKLSYEVRISQDGKSIYAR 811 M.
luteus IK B. subtilis E. coli P. aeruginosa MRSA S. pneumoniae E.
faecalis C. jeikeium PF-604 S. epidermidis LMEQVEV 812 C. albicans
C. jeikeium PF-605 S. epidermidis HYRWNTQWWKY 813 M. luteus P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium C. jejuni PF-607 S. epidermidis
YIESDPRKFDYIFGAIRDH 814 P. mirabilis E. coli MRSA S. pneumoniae C.
jeikeium PF-609 P. mirabilis TEIKLDNNEYLVLNLDDILGILK 815 E. coli S.
pneumoniae PF-610 S. epidermidis VFLKLKTSKIDLASIIFYP 816 M. luteus
P. mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae
E. faecalis C. jeikeium C. jejuni PF-612 S. epidermidis
GTTLKYGLERQLKIDIHPEITIINLNGGA 817 M. luteus DEFAKL P. mirabilis E.
coli P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-613 C. jeikeium ADEFAKL 818 PF-614 S. epidermidis
GLDIYA 819 E. coli C. jeikeium PF-615 S. epidermidis
FLNRFIFYIFTVKTKSALIKNLFLD 820 M. luteus P. mirabilis E. coli P.
aeruginosa C. albicans MRSA S. pneumoniae C. jeikeium C. jejuni
PF-616 C. jeikeium IVFVVTKEKK 821 PF-617 P. aeruginosa PMNAAEPE 822
C. albicans PF-619 S. epidermidis WSRVPGHSDTGWKVWHRW 823 M. luteus
B. subtilis P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium PF-621 S. epidermidis PPSSFLV
824 C. albicans PF-622 S. epidermidis TREDVFSVRLINNIVNKQA 825 P.
aeruginosa C. albicans S. pneumoniae E. faecalis C. jeikeium PF-623
S. epidermidis VLFAVYLGALDWLFSWLTQKM 826 P. aeruginosa MRSA S.
pneumoniae E. faecalis C. jeikeium PF-625 S. epidermidis
SDSTNNARTRKKARDVTTKDIDK 827 M. luteus S. pneumoniae C. jeikeium
PF-626 S. epidermidis KYDFDDFEPEEA 828 M. luteus E. coli C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-627 S.
epidermidis INDLLSYFTLHEK 829 P. aeruginosa MRSA S. pneumoniae E.
faecalis C. jeikeium PF-629 S. epidermidis GLAAIATVFALY 830 P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
PF-630 S. epidermidis IPATPIIHS 831 M. luteus P. mirabilis P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium
PF-631 S. epidermidis LIIYFSKTGNTARATRQI 832 P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-632 S.
epidermidis TTIQGVASLEKHGFRYTIIYPTRI 833 P. aeruginosa C. albicans
MRSA S. pneumoniae E. faecalis C. jeikeium PF-634 S. epidermidis
MPKARPVNHNKKKSKITIKSNFTLFYM 834 M. luteus FNP P. mirabilis E. coli
P. aeruginosa C. albicans MRSA S. pneumoniae E. faecalis C.
jeikeium PF-635 S. epidermidis MNAHGHSLIFQKMIVHAFAFFSKQKNY 835 P.
aeruginosa LYF C. albicans MRSA S. pneumoniae E. faecalis
C. jeikeium PF-636 S. epidermidis LVRLA 836 C. albicans MRSA S.
pneumoniae E. faecalis PF-637 S. epidermidis
SRIKQDARSVRKYDRIGIFFYSFKSA 837 P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium PF-638 S. epidermidis TFILPK 838
C. albicans MRSA C. jeikeium PF-639 S. pneumoniae QATQIKSWIDRLLVSED
839 C. jeikeium PF-640 C. albicans MGDINRNF 840 PF-641 S.
epidermidis SWKCHHLAIGGSWKCHHLAI 841 M. luteus E. coli C. albicans
MRSA E. faecalis C. jeikeium C. jejuni PF-642 M. luteus
FTTPMIGIPAGLLGGSYYLKRREEKGK 842 MRSA C. jeikeium PF-643
Mycobacteria spp VRCRL 843 PF-644 Mycobacteria spp TSGLIIGENGLNGL
844 PF-645 Mycobacteria spp SNSVQQG 845 PF-646 Mycobacteria spp
APASPGRRPG 846 PF-647 Mycobacteria spp GTFLGQKCAAATAS 847 PF-648 S.
mutans ARRYPAAGS 848 E. coli PF-649 Mycobacteria spp
CPRYPFVDVGPAGPWRARWRVGS 849 PF-650 Mycobacteria spp
IRSDQPGRQSRSSPRWPTGAGRHR 850 PF-651 Mycobacteria spp PRWPTGAGRHR
851 PF-652 Mycobacteria spp FLAPARPDLQAQRQALAQ 852 PF-653
Mycobacteria spp QSVHPLPAETPVADVI 853 PF-654 Mycobacteria spp
LSGRLAGRR 854 PF-655 M. smegmatis DAPCFDDQFGDLKCQMC 855 PF-656
Mycobacteria spp RGMFVPFHDVDCVQ 856 PF-657 Mycobacteria spp
YVANYTITQFGRDFDDRLAVAIHFA 857 PF-658 Mycobacteria spp
PTTPPPTTPPEIPTGGTVIST 858 PF-659 Mycobacteria spp TVIST 859 PF-660
Mycobacteria spp TDPQATAAPRRRTSPR 860 PF-661 Mycobacteria spp
PDEDIRRRAILPPAGPCRPMSPE 861 PF-662 Mycobacteria spp
GKQSRAHGPVASRREFRRKSG 862 PF-663 Mycobacteria spp ATLIPRKA 863
PF-664 M. smegmatis DQLCVEYPARVSTG 864 PF-665 Mycobacteria spp
VLRVATAVGEVPTGL 865 PF-666 Mycobacteria spp PNRRSRPR 866 PF-667
Mycobacteria spp PAHQRLRIDQRLVADRDMVQDYES 867 PF-668 Mycobacteria
spp TNAESMALAFRGRVHMSVNIAGLT 868 PF-669 Mycobacteria spp
RADRIESYPADGDRVITLWRNPYR 869 PF670 Mycobacteria spp TVIVAPMHSGV 870
PF-671 S. mutans TVSAFRTVH 871 E. coli PF-673 S. mutans VRRLRM 872
E. coli PF-674 S. mutans DGCDSEPALTYR 873 E. coli PF-675
Mycobacteria spp EIIPISPTRRCEMHTMSSAEYRGL 874 PF-676 S. mutans
AEYRGL 875 E. coli PF-677 Mycobacteria spp TCRGAGMH 876 PF-678
Mycobacteria spp RDRRWTRRDMYDWLESARV 877 PF-679 S. mutans CRARFIRR
878 E. coli PF-680 Mycobacteria spp ADPHPTTGI 879 PF-681 M.
smegmatis TALTTVGVSGARLITYCVGVEDI 880 PF-682 Mycobacteria spp
RRGKSEQGLSRR 881 PF-683 Mycobacteria spp LWPVA 882 PF-684
Mycobacteria spp RKLSLASGFALWRRSLV 883 PF-685 Mycobacteria spp
PTLWLACL 884 PF-686 M. smegmatis LAVLMGYIGYRGWSGKRHINRQ 885 PF-687
Mycobacteria spp AKRVLSLAVAPHRRQPVQGT 886 PF-688 Mycobacteria spp
ARNHAVIPAG 887 PF-689 S. mutans SAPSG 888 E. coli PF-690
Mycobacteria spp MIPLAGDPVSSHRTVEFGVLGTYLVSG 889 GSL PF-691
Mycobacteria spp HRTVEFGVLGTYLVSGGSL 890 PF-692 Mycobacteria spp
GVAREDPLEPDPLAPIIDDSR 891 PF-693 Mycobacteria spp PDPAR 892 PF-694
Mycobacteria spp DLIRPLYSMSAPSVA 893 PF-695 Mycobacteria spp
ALSVMLGNIPLVVPNANQL 894 PF-696 Mycobacteria spp IRSGISAAYARPLR 895
PF-697 Mycobacteria spp RADARAK 896 PF-698 Mycobacteria spp
SSGRAGVKCRRPTGR 897 PF-699 Mycobacteria spp GRAGVKCRRPTGR 898
PF-700 Mycobacteria spp LNWPFTGR 899 PF-701 S. mutans PRGAQSGHG 900
PF-702 Mycobacteria spp LSGRLAGRR 901 PF-703 Mycobacteria spp
MTTVDNIVGLVIAVALMAFLFAALLFPE 902 KF PF-704 Mycobacteria spp
APAARAAL 903 PF-705 S. mutans GEEEGTVAD 904 E. coli PF-706 L.
pneumophila LGYGAWIGCGLGLNGFHRID 905 PF-707 S. mutans
IDPESIVTTNNKQDNVDEQ 906 E. coli PF-709 S. mutans NKKHSPMD 907
PF-711 S. mutans KTAGPTGTIYKTN 908 PF-712 S. mutans
QIYRHVHKVQAKSANLRLY 909 E. coli PF-714 L. pneumophila FVVTQRMLRMYKK
910 PF-716 S. mutans HGENHHHKSDEKDNDSSEKKD 911 PF-717 E. coli
PQSEVTFENIYAPKANGGGLYGI 912 PF-720 S. mutans SLDMGK 913 PF-724 L.
pneumophila CYRFLTPKRPTRIS 914 PF-727 S. mutans AYARCRHDYPFTLGQMQTH
915 E. coli PF-728 S. mutans AIGQEQDRREYYYYSGYPYYY 916 E. coli
PF-731 L. pneumophila RHKLIRLPLSESVFCFLNNPKI 917 PF-732 E. coli
DRPSQTTHHTLSSSRITGPS 918 PF-733 S. mutans VISRQMGSEAVLELFIIM 919 E.
coli PF-735 S. mutans YDPLFPNDKN 920 E. coli PF-737 S. epidermidis
KSSGSSASASSTAGGSSSK 921 S. pneumoniae PF-738 S. epidermidis
KSGATSAASGAKSGASS 922 C. albicans C. jeikeium PF-741 S. epidermidis
AKREDTVAAQIGANILNLIQ 923 M. luteus P. mirabilis P. aeruginosa C.
albicans MRSA S. pneumoniae E. faecalis PF-744 S. epidermidis
LGVGTFVGKVLIKNQQKQKSKKKAQ 924 M. luteus E. coli MRSA S. pneumoniae
E. faecalis C. jeikeium PF-745 S. epidermidis
ANSQNSLFSNRSSFKSIFDKKSNITTNAT 925 M. luteus TPNSNIIIN C. albicans
PF-746 S. epidermidis FLGNSQYFTRK 926 M. luteus E. coli C. albicans
S. pneumoniae E. faecalis C. jeikeium PF-748 S. epidermidis
FQGFFDVAVNKWWEEHNKAKLWKNV 927 M. luteus KGKFLEGEGEEEDDE E. coli P.
aeruginosa
C. albicans MRSA S. pneumoniae E. faecalis C. jeikeium PF-749 S.
epidermidis GVNKWWEEHNKAKLWKNVKGKFLEG 928 M. luteus EGEEEDDE E.
coli P. aeruginosa C. albicans S. pneumoniae C. jeikeium PF-750 M.
luteus AESSPAKTTA 929 C. jeikeium PF-751 S. epidermidis AESSPAQETT
930 E. coli C. albicans C. jeikeium PF-752 S. epidermidis
LHVIRPRPELSELKFPITKILKVNKQGLKK 931 E. coli MRSA S. pneumoniae E.
faecalis PF-756 S. epidermidis DALLRLA 932 M. luteus C. albicans
MRSA C. jeikeium PF-757 M. luteus PQAISSVQQNA 933 C. albicans MRSA
PF-758 S. epidermidis PEIIKIVSGLL 934 M. luteus E. coli MRSA S.
pneumoniae E. faecalis C. jeikeium PF-760 S. epidermidis
DHITLDDYEIHDGFNFELYYG 935 M. luteus PF-761 S. epidermidis
SKFELVNYASGCSCGADCKCASETECK 936 M. luteus CASKK P. mirabilis P.
aeruginosa C. albicans MRSA S. pneumoniae E. faecalis PF-762 M.
luteus PAPAPSAPAPAPEQPEQPA 937 C. albicans PF-763 S. epidermidis
GIWMARNYFHRSSIRKVYVESDKEYER 938 M. luteus VHPMQKIQYEGNYKSQ E. coli
C. albicans MRSA S. pneumoniae E. faecalis PF-764 S. epidermidis
GYFEPGKRD 939 M. luteus C. albicans MRSA S. pneumoniae E. faecalis
C. jeikeium PF-765 S. epidermidis YLYWEVEHKPIIAKRDAYYAQLRKQKE 940
M. luteus IEEGA E. coli MRSA E. faecalis C. jeikeium PF-766 S.
epidermidis DAYYAQLRKQKEIEEGA 941 M. luteus C. albicans MRSA E.
faecalis C. jeikeium PF-767 S. epidermidis DGKQGEPVALKPTDN 942 M.
luteus E. coli MRSA S. pneumoniae E. faecalis C. jeikeium PF-768 S.
epidermidis GFRGGKRGGARG 943 S. pneumoniae E. faecalis C. jeikeium
PF-770 S. epidermidis GVGIGFIMMGVVGYAVKLVHIPIRYLIV 944 M. luteus P.
mirabilis E. coli P. aeruginosa C. albicans MRSA S. pneumoniae E.
faecalis C. jeikeium PF-772 S. epidermidis TKESSS 945 C. albicans
MRSA S. pneumoniae C. jeikeium PF-773 S. epidermidis TLKESK 946 C.
albicans C. jeikeium PF-776 S. epidermidis
VSILLYLSATIILPNVLRLLVARAIIVRV 947 M. luteus P. mirabilis C.
albicans MRSA S. pneumoniae E. faecalis PF-777 Mycobacteria spp.
PGADGKLAEASAAIARLVRS 948 PF-778 Mycobacteria spp. MNLILTAHGT 949
PF-779 Mycobacteria spp. IYGDFFNFYLCDISLKVNGLQPGGPVRT 950
VKLFGQPTGRCTPQ PF-780 Mycobacteria spp. AVYDALVALAAAEHRAELATRDARAK
951 DTYEKIGVHVVVAA PF-781 Mycobacteria spp. PLVVVNHRRAERSRG 952
PF-782 Mycobacteria spp. TGPRRGIDLTSNRALSEVLDEGLELNSRK 953 PF-783
Mycobacteria spp. FTSEVRGVFTYRVNKAGLITNMRGYW 954 NLDMMTFGNQE PF-784
Mycobacteria spp. MAMTTVDNIVGLVIAVALMAFLFAALL 955 FPEKF PF-785
Mycobacteria spp. MRPQHSPAGKAFVVKKITHEQS 956 PF-786 Mycobacteria
spp. LSERERRRLKRGII 957 PF-787 Mycobacteria spp.
MTERQRRALLKQHPEVVSWSDYLEKR 958 KRRTGTAG PF-788 Mycobacteria spp.
GLITVFAGTARILQLRRAAKKTHAAALR 959 PF-789 Mycobacteria spp. PRGAQSGHG
960 PF-790 Mycobacteria spp. PAGPDHLDQRDHR 961 PF-791 S. mutans
IFLTTQNTDYSEHNAA 962 PF-792 S. mutans ALHASGIQAI 963 PF-793 S.
mutans YTQUNNASAYAMLLTNKDTVP 964 PF-794 S. mutans NLYFENQGN 965
PF-795 S. mutans ALHKSGIQVIADWVPDQIYN 966 PF-796 S. mutans
YTQSNIPTAYALMLSNKDSI 967 PF-797 S. mutans WYYFDNNGYM 968 PF-798 S.
mutans ALHSKGIKVMADWVPDQMYA 969 PF-799 S. mutans
YTHYNTALSYALLLTNKSSVP 970 PF-800 S. mutans WYYFDNNGYM 971 PF-C003
A. naeslundii FCSVDHDVITIAADHVKQGAEA 972 P. gingivalis S. mutans
PF-C008 A. naeslundii AQPRRTWLVNFGEVPSPGLTNDGMPDH 973 PF-C034 S.
mutans HPMPITVRSRKPGPLTAPSEH 974 E. coli PF-C045 A. naeslundii
FREGMGWPLSNEGSPTAPLPKHRNQV 975 T. denticola PF-C050 A. naeslundii
QGLARPVLRRIPL 976 S. mutans PF-C052 A. naeslundii SRFRNGV 977 F.
nucleatum S. mutans PF-C055 A. naeslundii YNLSIYIYFLHTITIAGLITLPFII
978 F. nucleatum P. gingivalis S. mutans PF-C057 A. naeslundii
YFWWYWVQDCIPYKNNEVWLELSNN 979 F. nucleatum MK P. gingivalis S.
mutans PF-C058 A. naeslundii FETGFGDGYYMSLWGLNEKDEVCKVV 980 F.
nucleatum IPFINPELID P. gingivalis S. mutans PF-C061 A. naeslundii
TLNYKKMFFSVIFLLGLNYLICNSPLFFK 981 F. nucleatum QIEF P. gingivalis
S. mutans T. denticola PF-C062 A. naeslundii
PLARATEVVATLFIICSLLLYLTR 982 F. nucleatum P. gingivalis S. mutans
T. denticola PF-C063 A. naeslundii SHFRKGD 983 F. nucleatum S.
mutans PF-C064 A. naeslundii DEEALEMGANLYAQFAIDFLNSKK 984 F.
nucleatum P. gingivalis S. mutans T. denticola PF-C065 A.
naeslundii DEERYSDSYFLKEKVFYLILALFLILFHQ 985 F. nucleatum
KYLYFLEIITI P. gingivalis S. mutans PF-C068 A. naeslundii LNLFASI
986 F. nucleatum S. mutans
PF-C069 A. naeslundii NALMLREMQLAKNIKVEVTDVLSNKK 987 F. nucleatum
YC P. gingivalis S. mutans T. denticola PF-C071 A. naeslundii
QVIVKIL 988 F. nucleatum S. mutans PF-C072 A. naeslundii
KKMFSLIRKVNWIFFILFIVLDLTNVFPLI 989 F. nucleatum RTILFAILSRQ P.
gingivalis S. mutans T. denticola PF-C075 A. naeslundii
KALVISVFAIVFSIIFVKFFYWRDKK 990 F. nucleatum P. gingivalis S. mutans
T. denticola PF-C080 A. naeslundii INIPGLF 991 F. nucleatum S.
mutans PF-C084 A. naeslundii FFSVIFLFGLNYLICNSPLFNILR 992 F.
nucleatum P. gingivalis S. mutans PF-C085 A. naeslundii
KKFKIFVIINWFYHKYIILNFEENF 993 F. nucleatum P. gingivalis S. mutans
T. denticola PF-C086 A. naeslundii ELFFTILSDCNELFLLHLLQQPLFYIKKGK
994 F. nucleatum P. gingivalis S. mutans T. denticola PF-C088 A.
naeslundii DIANNILNSVSERLIIA 995 F. nucleatum P. gingivalis S.
mutans T. denticola PF-C091 A. naeslundii
ASNTPRFVRLTLFNFYSKIWNVTHLFLF 996 F. nucleatum NNL P. gingivalis S.
mutans T. denticola PF-C093 A. naeslundii EKLGTMV 997 F. nucleatum
S. mutans PF-C095 A. naeslundii LLALNMNEDTYYFELFFIFDNQNKKWL 998 F.
nucleatum IFDLKERG P. gingivalis S. mutans PF-C098 A. naeslundii
PETKGKVSAFVFGIVVANVIAVVYILYM 999 F. nucleatum LREIGIIQ P.
gingivalis S. mutans T. denticola PF-C120 A. naeslundii
ASLSTMTFKVMELKELIILLCGLTMLMI 1000 F. nucleatum QTEFV P. gingivalis
S. mutans T. denticola PF-C131 A. naeslundii
QWIVAKREIRMHIYCHISVIHVIIFFG 1001 F. nucleatum P. gingivalis S.
mutans PF-C134 A. naeslundii NELMKYPATLTATATTPGIKYSHLCSVCL 1002 F.
nucleatum P. gingivalis S. mutans T. denticola PF-C135 A.
naeslundii KNTHAYLRVLRLSSLILSYQASVYPLFA 1003 F. nucleatum YLCQQKDY
P. gingivalis S. mutans PF-C136 A. naeslundii
LILSYQASVYPLFAYLCQQKDY 1004 F. nucleatum P. gingivalis S. mutans T.
denticola PF-C137 A. naeslundii QRMYWFKRGFETGDFSAGDTFAELK 1005 F.
nucleatum P. gingivalis S. mutans PF-C139 A. naeslundii
LLASHPERLSLGVFFVYRVLHLLLENT 1006 F. nucleatum P. gingivalis S.
mutans T. denticola PF-C142 A. naeslundii
DFPPLSFFRRRFHAYTAPIDNFFGANPF 1007 F. nucleatum P. gingivalis S.
mutans T. denticola PF-C143 A. naeslundii VVFGGGDRLV 1008 F.
nucleatum P. gingivalis S. mutans T. denticola PF-C145 A.
naeslundii YGKESDP 1009 F. nucleatum P. gingivalis S. mutans T.
denticola PF-C160 F. nucleatum AASGFTYCASNGVWHPY 1010 PF-C180 F.
nucleatum TVEELDKAFTWGAAAALAIGVIAINVG 1011 P. gingivalis
LAAGYCYNNNDVF S. mutans T. denticola PF-C181 P. gingivalis
KMRAGQVVFIYKLILVLLFYVLQKLFD 1012 LKKGCF PF-C194 A. naeslundii
NTNDLLQAFELMGLGMAGVFIVLGILYI 1013 F. nucleatum VAELLIKIFPVNN P.
gingivalis S. mutans T. denticola PF-C259 F. nucleatum AEIQPHCLSVL
1014 S. mutans PF-C271 A. naeslundii FFPSYYSIIITYF 1015 F.
nucleatum P. gingivalis S. mutans T. denticola PF-C273 A.
naeslundii KNMLKRRMKQKRLFDEEDRLRVLSKY 1016 P. gingivalis TKSYY S.
mutans T. denticola PF-C281 A. naeslundii
KKEKLLTAIRLQHRAEIRGYFTIFFLFFRI 1017 F. nucleatum P. gingivalis S.
mutans T. denticola PF-C285 A. naeslundii
FTIIELKKQKIKHGENNKKTAHPLNEPF 1018 F. nucleatum CARA P. gingivalis
S. mutans T. denticola PF-C290 A. naeslundii
GNVHPESDFHNLIQFIKTFLYFTIFFKYFL 1019 F. nucleatum P. gingivalis S.
mutans T. denticola PF-C291 A. naeslundii
HPFLTGTGCPLFLIFRLFFVKAYFSFTVF 1020 F. nucleatum P. gingivalis S.
mutans PF-S003 S. epidermidis ALALLKQDLLNFEGRGRIITSTYLQFNE 1021 M.
luteus GCVP P. mirabilis E. coli P. aeruginosa C. albicans MRSA S.
pneumoniae E. faecalis C. jeikeium C. jejuni M. smegmatis PF-S004
S. epidermidis VLLNIFRTLLEFFSPSNAPGAEDVPLPDT 1022 MRSA QA C.
jeikeium PF-S007 S. epidermidis VVAGVVLLTALAVGSKRKEKKQIKEIQ 1023
MRSA RLLAATR PF-S015 S. epidermidis IENLERGARRPP 1024 MRSA C.
jeikeium PF-S018 S. epidermidis GMPQIPRLRI 1025 M. luteus C.
albicans MRSA E. faecalis C. jeikeium C. jejuni PF-S023 S.
epidermidis MAEDERRALKRRTNRGRTRTRKRITV 1026 MRSA PF-S026 S.
epidermidis TELKYNGEEYLLLTQRDILAVIEK 1027 MRSA C. jeikeium PF-S029
M. luteus TSDTQSQSPWLFDNADIVNIYPVQLMHS 1028 P. mirabilis SDND E.
coli C. albicans C. jeikeium C. jejuni * Peptide binding was
conducted in aqueous buffers that varied depending on peptide
solubility. For example: Brain Heart Infusion (BHI) Media; 1X
Phosphate-buffered saline (PBS); 0.05% v/v Tween-20; 0.05% v/v
Tween-80; 1% v/v Glycerol; 50 .mu.M Guanidine hydrochloride; 0.05%
v/v Acetic acid; 50 .mu.M Urea; 1% v/v Polyethylene glycol 400 (PEG
400); 20 mM Sodium glutamate; 50 mM
Piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES); 50 mM Sodium
acetate; 1% v/v Pluronic 17R4; 1% w/v Pluronic F108; 1% w/v
Pluronic P123; 0.2% v/v Cetyl trimethylammonium bromide (CTAB);
0.8% v/v .beta.-D-Octyl glucoside (BOG); 0.2% CTAB and 0.05%
Tween-20; 0.2% CTAB and 0.05% Tween-80; 0.2% CTAB and 1% glycerol;
and 20 mM HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic
acid), 150 mM sodium chloride, 1 mM magnesium chloride and 0.1%
CTAB. Preferably, binding was evaluated in 1x PBS. ** Three-amino
acid code: Dab: Diaminobutyric acid; Orn: Ornithine; cDOrn, cOrn:
side-chain cyclical Ornithine; Abreviations: c(X . . . Y) indicates
amino acids are cyclic, connected X to Y; DX indicates D-isoform
amino acids.
[0093] In certain embodiments, the amino acid sequence of the
targeting peptides comprises or consists of a single amino acid
sequence, e.g., as listed above in Table 3. In certain embodiments
the amino acid sequence of the targeting peptides comprises two
copies, three copies, four copies, five copies six copies or more
of one or more of the amino acid sequences listed in Table 3,
and/or Table 10, and/or Table 12. Thus, compound targeting
constructs are contemplated where the construct comprises multiple
domains each having targeting activity. The targeting domains
comprising such a construct can be the same or different. In
certain embodiments the construct comprises at least 2, at least 3,
at least 4, at least 5, at least 6, at least 7, or at least 8
different targeting domains each domain comprising a different
targeting sequence.
[0094] Various targeting domains comprising such a construct can be
joined directly to each other or two or more of such domains can be
attached to each other via a linker. An illustrative, but
non-limiting, list of suitable linkers is provided in Table 16.
Thus, in certain embodiments, two or more targeting domains
comprising a compound/multiple targeting construct are chemically
conjugated together.
[0095] In certain embodiments the two or more targeting domains
comprising the construct are joined by a peptide linker. Where all
the targeting domains are attached directly to each other or are
joined by peptide linkers, the entire construct can be provided as
a single-chain peptide (fusion protein).
[0096] In various embodiments, the targeting peptides described
herein comprise one or more of the amino acid sequences shown in
Table 3, and/or Table 10, and/or Table 12 (and/or the retro,
inverso, retroinverso, etc. forms of such sequences). In certain
embodiments the peptides range in length up to about 100 amino
acids in length, preferably up to about 80, about 70, about 60, or
about 51 amino acids in length. In certain embodiments the peptides
range in length from about 8 amino acids up to about 100 amino
acids 80 amino acids, 60 amino acids or about 51 amino acids in
length. In certain embodiments the peptides range in length from
about 8 up to about 50, 40, 30, 20, 15, 15, 13, or 12 amino acids
in length.
[0097] As shown in Tables 3, 10, and 12 the various amino acid
sequences described herein target particular microorganisms. The
range of activity of the peptides or compositions comprising such
peptides can be increased by including amino acid sequences that
target different microorganisms either as separate components
and/or as multiple domains within a single construct.
[0098] In some embodiments greater specificity and/or avidity can
be obtained by including multiple different amino acid sequences
that target the same microorganism.
II. Antimicrobial Peptides.
[0099] A) Uses of Antimicrobial Peptides.
[0100] The antimicrobial peptides described herein also have a wide
variety of uses. For example, the peptides can be formulated
individually, in combination, in combination with other
antimicrobial peptides, and/or in combination with various
antibacterial agents to provide antimicrobial pharmaceuticals.
[0101] In various embodiments, the antimicrobial peptides described
herein can be formulated individually, in combination, in
combination with other antimicrobial peptides, and/or in
combination with various antibiotic (e.g., antibacterial) agents in
"home healthcare" formulations. Such formulations include, but are
not limited to toothpaste, mouthwash, tooth whitening strips or
solutions, contact lens storage, wetting, or cleaning solutions,
dental floss, toothpicks, toothbrush bristles, oral sprays, oral
lozenges, nasal sprays, aerosolizers for oral and/or nasal
application, wound dressings (e.g., bandages), and the like.
[0102] In various embodiments the antimicrobial peptides described
herein can be formulated individually, in combination, in
combination with other antimicrobial peptides, and/or in
combination with various antibiotic (e.g., antibacterial) agents in
various cleaning and/or sterilization formulations for use in
agriculture, in fool preparation and transport, in the home,
workplace, clinic, or hospital.
[0103] In certain embodiments the antimicrobial peptides described
herein are attached to one or more targeting moieties to
specifically and/or to preferentially deliver the peptide(s) to a
target (e.g. a target microorganism, biofilm, bacterial film,
particular tissue, etc.).
[0104] Other possible uses of the targeting and/or antimicrobial
peptides disclosed herein include, but are not limited to biofilm
dispersal, biofilm retention, biofilm formation, anti-biofilm
formation, cell agglutination, induction of motility or change in
motility type, chemoattractant or chemorepellent, extracellular
signal for sporogenesis or other morphological change, induction or
inhibition of virulence gene expression, utilized as extracellular
scaffold, adhesin or binding site, induction or suppression of host
immune response, induction or suppression of bacterial/fungal
antimicrobial molecule production, quorum-sensing, induction of
swarming behavior, apoptosis or necrosis inducing in eukaryotic
cells, affecting control of or inducing the initiation of cell
cycle in eukaryotes, in archaea or prokaryotes, induces autolysis
or programmed cell death, inhibition of phage/virus attachment or
replication, evasion of innate immunity, induction or inhibition of
genetic transformation or transduction competence, induction or
inhibition of pilus-mediated conjugation, induction or inhibition
of mating behavior in bacteria and fungi, induction or inhibition
of nodule formation or metabolic compartmentalization, metal, ion,
or nutrient binding, acquisition or inhibition of metal, ion, or
nutrient binding and acquisition, and the like.
[0105] In certain embodiments, compositions and methods are
provided for decreasing the infectivity, morbidity, and rate of
mortality associated with a variety of pathogens. The present
invention also relates to methods and compositions for
decontaminating areas, samples, solutions, and foodstuffs colonized
or otherwise infected by pathogens and microorganisms. Certain
embodiments of the present compositions are nontoxic and may be
safely ingested by humans and other animals. Additionally, certain
embodiments of the present invention are chemically stable and
non-staining.
[0106] In some embodiments, the present invention provides
compositions and methods suitable for treating animals, including
humans, exposed to pathogens or the threat of pathogens. In some
embodiments, the animal is contacted with effective amounts of the
compositions prior to exposure to pathogenic organisms. In other
embodiments, the animal or human is contacted with effective
amounts of the compositions after exposure to pathogenic organisms.
Thus, the present invention contemplates both the prevention and
treatment of microbiological and other infections.
[0107] In certain embodiments compositions and methods are provided
for decontaminating solutions and surfaces, including organic and
inorganic samples that are exposed to pathogens or suspected of
containing pathogens. In still other embodiments of the present
invention, the compositions are used as additives to prevent the
growth of harmful or undesired microorganisms in biological and
environmental samples.
[0108] These applications of the peptides described herein are
intended to be illustrative and not limiting. Using the teaching
provided herein, other uses will be recognized by one of skill in
the art.
[0109] B Illustrative Novel Antimicrobial Peptides.
[0110] Antimicrobial peptides (also called host defense peptides)
are an evolutionarily conserved component of the innate immune
response and are found among all classes of life. Unmodified, these
peptides are potent, broad spectrum antibiotics which demonstrate
potential as novel therapeutic agents. Antimicrobial peptides have
been demonstrated to kill Gram-negative and Gram-positive bacteria
(including strains that are resistant to conventional antibiotics),
mycobacteria (including Mycobacterium tuberculosis), enveloped
viruses, and fungi.
[0111] Naturally-occurring antimicrobial peptides are typically
short peptides, generally between 12 and 50 amino acids. These
peptides often include two or more positively charged residues
provided by arginine, lysine or, in acidic environments, histidine,
and frequently a large proportion (generally >50%) of
hydrophobic residues (see, e.g., Papagianni et al. (2003)
Biotechnol Adv 21: 465; Sitaram and Nagaraj (2002) Curr Pharm Des
8: 727; Durr et al. (2006) Biochim. Biophys. Acta 1758:
1408-1425).
[0112] Frequently the secondary structures of these molecules
follow 4 themes, including i) .alpha.-helical, ii) .beta.-stranded
due to the presence of 2 or more disulfide bonds, iii)
.beta.-hairpin or loop due to the presence of a single disulfide
bond and/or cyclization of the peptide chain, and iv) extended.
Many of these peptides are unstructured in free solution, and fold
into their final configuration upon partitioning into biological
membranes. The ability to associate with membranes is a definitive
feature of antimicrobial peptides although membrane
permeabilisation is not necessary. These peptides have a variety of
antimicrobial activities ranging from membrane permeabilization to
action on a range of cytoplasmic targets.
[0113] The modes of action by which antimicrobial peptides kill
bacteria is varied and includes, but is not limited to disrupting
membranes, interfering with metabolism, and targeting cytoplasmic
components. In many cases the exact mechanism of killing is not
known.
[0114] In certain embodiments the antimicrobial peptides include
peptides comprising or consisting of one or more of the amino acid
sequences shown in Tables 4 (SEQ ID NOs:1029-1078), and/or Table 5
(SEQ ID NOs:1079-1566). In various embodiments the peptides include
peptides comprising or consisting of the retro, inverso,
retro-inverso, and/or beta form of one or more of the amino acid
sequences shown in Tables 4 (SEQ ID NOs:1029-1078), and/or Table 5
(SEQ ID NOs:1079-1566). The peptides can comprise all "L" amino
acids, all "D" amino acids, or combinations of "L" and "D" amino
acids. Also contemplated are circular permutations of these
sequences as well as peptides comprising or consisting of the
retro, inverso, retro-inverso, and/or beta form of such circular
permutations.
[0115] It will also be recognized, that in certain embodiments, any
peptide or compound AMP described herein can be circularized.
[0116] In various embodiments the peptides can optionally bear one
or more protecting groups, e.g., and the amino and/or carboxyl
termini, and/or on side chains.
[0117] Also contemplated are peptides comprising one, two, three
four, or five conservative substitutions of these amino acid
sequences.
TABLE-US-00004 TABLE 4 Novel antimicrobial peptides, target
microorganisms and MIC values. Organism MIC SEQ ID (.mu.M)
Structure/sequence ID NO K-1 S. mutans, 25 GLGRVIGRLIKQIIWRR 1029
K-2 S. mutans, 12.5 VYRKRKSILKIYAKLKGWH 1030 K-7 S. mutans, 12.5
NYRLVNAIFSKIFKKKFIKF 1031 K-8 S. mutans, 4 KILKFLFKKVF 1032 K-9 S.
mutans, 4 FIRKFLKKWLL 1033 K-10 S. mutans, 4 KLFKFLRKHLL 1034 K-11
S. mutans, 4 KILKFLFKQVF 1035 K-12 S. mutans, 8 KILKKLFKFVF 1036
K-13 S. mutans, 16 GILKKLFTKVF 1037 K-14 S. mutans, 8 LRKFLHKLF
1038 K-15 S. mutans, 4 LRKNLRWLF 1039 K-16 S. mutans, 8 FIRKFLQKLHL
1040 P. aeruginosa, 12.5 MRSA, 25 K-17 S. mutans, 8 FTRKFLKFLHL
1041 K-18 S. mutans, 16 KKFKKFKVLKIL 1042 K-19 S. mutans, 16
LLKLLKLKKLKF 1043 K-20 S. mutans, 8 FLKFLKKFFKKLKY 1044 K-21 S.
mutans, 8 GWLKMFKKIIGKFGKF 1045 K-22 S. mutans, 8 GIFKKFVKILYKVQKL
1046 1T-88 GRLVLEITADEVKALGEALANAKI 1047 PF-531 A. baumannii, 25
YIQFHLNQQPRPKVKKIKIFL-NH2 1048 P. aeruginosa, 50 T. rubrum, 50 A.
niger, 25 B. subtilis, 25 C. difficile, 12.5 C. jeikeium, 6.25 S.
epidermidis, 50 S. mutans, 12.5 PF-527 P. aeruginosa, 50
GSVIKKRRKRMAKKKHRKLLKKTRIQR 1049 T. rubrum, 25 RRAGK A. niger, 50
B. subtilis, 12.5 C. jeikeium, 6.25 MRSA, 50 S. epidermidis, 25
PF-672 C. albicans, 1.56 MRFGSLALVAYDSAIKHSWPRPSSVRR 1050 T.
rubrum, 0.78 LRM A. niger, 3 B. subtilis, 0.78 E. faecalis, 3.13
MRSA, 1.56 S. epidermidis, 0.39 PF-606 E. coli, 50
FESKILNASKELDKEKKVNTALSFNSHQ 1051 MRSA, 50 DFAKAYQNGKI S.
epidermidis, 50 S. mutans, 50 S. pneumoniae, 50 PF-547 T. rubrum,
25 WSRVPGHSDTGWKVWHRW-NH2 1052 B. subtilis, 25 S. mutans, 12.5
PF-006 A. baumannii, 50 MGIIAGIIKFIKGLIEKFTGK 1053 B. subtilis, 25
MRSA, 50 PF-545 A. niger, 50 RESKLIAMADMIRRRI-NH2 1054 B. subtilis,
25 MRSA, 50 PF-278 C. albicans, 50 LSLATFAKIFMTRSNWSLKRFNRL 1055 T.
rubrum, 50 S. epidermidis, 50 PF-283 T. rubrum, 50
MIRIRSPTKKKLNRNSISDWKSNTSGRF 1056 B. subtilis, 50 FY S.
epidermidis, 50 PF-307 C. albicans, 50 MKRRRCNWCGKLFYLEEKSKEAYCCK
1057 T. rubrum, 50 ECRKKAKKVKK B. subtilis, 50 PF-168 T. rubrum, 50
VLPFPAIPLSRRRACVAAPRPRSRQRAS 1058 A. niger, 50 MRSA, 50 PF-538 A.
baumannii, 25 KNKKQTDILEKVKEILDKKKKTKSVGQ 1059 C. difficile, 25 KLY
PF-448 A. niger, 25 SLQSQLGPCLHDQRH 1060 S. pneumoniae, 50 PF-583
MRSA, 50 KFQGEFTNIGQSYIVSASHMSTSLNTGK 1061 S. epidermidis, 50
PF-600 E. coli, 50 TKKIELKRFVDAFVKKSYENYILERELK 1062 S. pneumoniae,
50 KLIKAINEELPTK PF-525 A. niger, 50 KFSDQIDKGQDALKDKLGDL 1063 S.
pneumoniae, 50 PF-529 A. niger, 50 LSEMERRRLRKRA-NH2 1064 S.
pneumoniae, 50 PF-148 A. niger, 50 RRGCTERLRRMARRNAWDLYAEHFY 1065
B. subtilis, 50 PF-530 A. baumannii, 25 SKFKVLRKIIIKEYKGELMLSIQKQR
1066 PF-522 C. difficile, 25 FELVDWLETNLGKILKSKSA-NH2 1067 PF-497
B. subtilis, 50 LVLRICTDLFTFIKWTIKQRKS 1068 PF-499 B. subtilis, 50
VYSFLYVLVIVRKLLSMKKRIERL 1069 PF-322 B. subtilis, 50
GIVLIGLKLIPLLANVLR 1070 PF-511 S. pneumoniae, 50
VMQSLYVKPPLILVTKLAQQN 1071 PF-512 S. pneumoniae, 50
SFMPEIQKNTIPTQMK 1072 PF-520 S. pneumoniae, 50
LGLTAGVAYAAQPTNQPTNQPTNQPTN 1073 QPTNQPTNQPRW-NH2 PF-521 S.
pneumoniae, 50 CGKLLEQKNFFLKTR 1074 PF-523 S. pneumoniae, 50
ASKQASKQASKQASKQASKQASRSLKN 1075 HLL PF-524 S. pneumoniae, 50
PDAPRTCYHKPILAALSRIVVTDR 1076 PF-209 MRSA, 50 NYAVVSHT 1077 PF-437
S. pneumoniae, 50 FQKPFTGEEVEDFQDDDEIPTII 1078
Where protecting groups are shown (e.g., --NH.sub.2) they are
optional. Conversely any peptide shown without protecting groups
can bear one or more such groups.
[0118] In certain embodiments peptides that induce alterations in
phenotype or other biological activities can also be used as
antimicrobial effector moieties. Illustrative alternative peptides
are shown in Table 5.
TABLE-US-00005 TABLE 5 Illustrative list of novel morphology,
biofilm and growth disrupting peptides. SEQ ID ID Organism, effect
Structure/sequence NO G-1 S. mutans: Ca2+ DSSQSDSDSDSNSSNTNSNSSITNG
1079 binding G-2 S. mutans: biofilm LPGTLHIQAEFPVQLEAGSLIQIFD 1080
structure G-4 S. mutans: EIPIQLANDLANYYDISLDSIFFW 1081 Biofilm
structure G-5 M. xanthus: RDMTVAGKRPNFLIITTDEE 1082 Altered cell
morphology G-6 M. xanthus: NTSIVCAVTFAPIKEVPLLWRAGLTLRS 1083
Altered cell RQS morphology G-7 M. xanthus:
QAKVEREVERDLVYTLRRLCDPSGSER 1084 Altered cell TK morphology G-8 S.
mutans: PRMIDIISFHGCHGDHQVWTDPQATAL 1085 Altered biofilm PR
structure PF-001 S. epidermidis (C) MNNWIIVAQLSVTVINEIIDIMKEKQKG
1086 M. luteus (C) GK MRSA (R) C. jeikeium (D) PF-002 B. subtilis
(R) NDDAQ 1087 S. pneumoniae (H) PF-003 S. epidermidis (D)
MNNWIKVAQISVTVINEVIDIMKEKQN 1088 M. luteus (A) GGK MRSA (R) C.
jeikeium (A) PF-004 S. epidermidis (A) ARLSKAIIIAVIVVYHLDVRGLF 1089
M. luteus (A) MRSA (R) C. jeikeium (A) PF-005 B. subtilis (C)
MESIFKIKLMNGICRSENMNMKKKNK 1090 S. pneumoniae (H) GEKI PF-006 S.
epidermidis (D) MGIIAGIIKFIKGLIEKFTGK 1091 M. luteus (A) B.
subtilis (I) MRSA (I) S. pneumoniae (R) C. jejuni (D) PF-007 S.
epidermidis (A) MGIIAGIIKVIKSLIEQFTGK 1092 M. luteus (A) E. coli
(A) MRSA (R) E. faecalis (A) PF-008 B. subtilis (D)
MIEIGSIAYLNGGSKKYNHILNQENR 1093 C. jejuni (R) PF-009 S. epidermidis
(S) SKKYNHILNQENR 1094 PF-010 S. epidermidis (S)
MDIDVNKLLQAFVYFKSFEKLRHNNS 1095 M. luteus (A) MRSA (R) C. jeikeium
(A) PF-011 MRSA (R) MFCYYKQHKGDNFSIEEVKNIIADNEM 1096 C. jeikeium
(C) KVN PF-012 S. epidermidis (S) WRGPNTEAGGKSANNIVQVGGAPT 1097 M.
luteus (C) MRSA (R) C. jeikeium (A) PF-013 S. epidermidis (C)
LIQKGLNQTFIVVIRLNNFIKKS 1098 M. luteus (D) MRSA (R) C. jeikeium (D)
PF-015 MRSA (W) SIDKRNLYNLKYYE 1099 PF-017 MRSA (M) ESIIE 1100
PF-019 MRSA (M) NDTNK 1101 PF-020 S. mutans (F)
MKIILLLFLIFGFIVVVTLKSEHQLTLFSI 1102 S. epidermidis (C) M. luteus
(C) MRSA (C) S. pneumoniae (D) PF-021 S. epidermidis (A)
FSLNFSKQKYVTVN 1103 M. luteus (A) MRSA (R) C. jeikeium (R) PF-022
S. epidermidis (D) MINELKNKNSGIMNNYVVTKESKL 1104 M. luteus (A) MRSA
(R) C. jeikeium (A) PF-023 MRSA (S) MTKNTIISLENEKTQINDSENESSDLRK
1105 AK PF-024 S. epidermidis (D) DLRKAK 1106 MRSA (M) PF-025 S.
epidermidis (S) LLIIFRLWLELKWKNKK 1107 M. luteus (A) MRSA (R) C.
jeikeium (A) PF-026 MRSA (M) SIHFIN 1108 PF-027 S. epidermidis (D)
HNARKYLEFISQKIDGDKLTKEDSL 1109 MRSA (M) PF-028 S. epidermidis (M)
ALDCSEQSVILWYETILDKIVGVIK 1110 MRSA (R) C. jeikeium (M) PF-029 MRSA
(M) NSTNE 1111 PF-030 S. epidermidis (D) MTCHQAPTTTHQSNMA 1112 M.
luteus (C) MRSA (R) C. jeikeium (C) PF-031 MRSA (M)
MPHHSTTSSRIVVPAHQSNMASTPNLSI 1113 TP PF-032 S. epidermidis (S)
RIVVPAHQSNMASTPNLSITP 1114 C. jeikeium (C) PF-033 S. epidermidis
(M) MFIFKTTSKSHFHNNVKSLECIKIPINK 1115 B. subtilis (C) NR MRSA (M)
S. pneumoniae (R) C. jeikeium (D) C. jejuni (R) PF-034 S.
epidermidis (A) EPKKKHFPKMESASSEP 1116 PF-035 MRSA (M) SFYESY 1117
PF-036 S. epidermidis (S) ILNRLSRIVSNEVTSLIYSLK 1118 M. luteus (A)
MRSA (R) C. jeikeium (A) PF-037 S. epidermidis (D)
MTKKRRYDTTEFGLAHSMTAKITLHQ 1119 M. luteus (C) ALYK MRSA (R) C.
jeikeium (D) PF-040 S. mutans (F) MIHLTKQNTMEALHFIKQFYDMFFILN 1120
S. epidermidis (D) FNV M. luteus (D) B. subtilis (D) P. mirabilis
(C) E. coli (C) MRSA (D) S. pneumoniae (D) C. jeikeium (D) C.
jejuni (D) PF-041 S. epidermidis (R) ELLVILPGFI 1121 MRSA (M)
PF-042 S. epidermidis (D) LLLSYFRYTGALLQSLF 1122 M. luteus (C) MRSA
(R) C. jeikeium (S) PF-043 S. epidermidis (D)
MIKNETAYQMNELLVIRSAYAK 1123 M. luteus (C) MRSA (R) C. jeikeium (A)
PF-045 MRSA (S) LDINDYRSTY 1124 PF-046 S. epidermidis (C)
LDFYLTKHLTLML 1125 MRSA (R) C. jeikeium (R) PF-048 S. epidermidis
(D) LYFAFKKYQERVNQAPNIEY 1126 MRSA (W) C. jeikeium (S) PF-049 MRSA
(S) AYYLKRREEKGK 1127 PF-051 S. mutans (D)
RFFNFEIKKSTKVDYVFAHVDLSDV 1128 S. epidermidis (D) M. luteus (C)
MRSA (D) S. pneumoniae (D) PF-052 S. epidermidis (S)
QELINEAVNLLVKSK 1129 M. luteus (A) MRSA (R) C. jeikeium (D) PF-053
S. epidermidis (C) KLFGQWGPELGSIYILPALIGSIILIAIVT 1130 M. luteus
(D) LILRAMRK B. subtilis (H) E. coli (A) P. aeruginosa (A) C.
albicans (A) MRSA (D) S. pneumoniae (S) E. faecalis (A) C. jeikeium
(D) C. jejuni (D) PF-056 S. epidermidis (D)
AEQLFGKQKQRGVDLFLNRLTIILSILF 1131 M. luteus (D) FVLMICISYLGM B.
subtilis (C) C. albicans (B) MRSA (M) S. pneumoniae (D) C. jeikeium
(S) C. jejuni (D) PF-057 S. epidermidis (D) TMIVISIPRFEEYMKARHKKWM
1132 M. luteus (C) E. coli (M) C. albicans (A) MRSA (M) S.
pneumoniae (R) E. faecalis (A) C. jeikeium (A) C. jejuni (D) PF-058
MRSA (M) FADQSQDNA 1133 PF-059 C. jejuni (C)
TITLKAGIERALHEEVPGVIEVEQVF 1134 PF-061 S. epidermidis (R)
GYNSYKAVQDVKTHSEEQRVTAKK 1135 B. subtilis (R) S. pneumoniae (R)
C. jejuni (R) PF-063 S. epidermidis (R) IAAIIVLVLFQKGLLQIFNWILIQLQ
1136 M. luteus (R) B. subtilis (C) P. aeruginosa (A) MRSA (M) S.
pneumoniae (D) C. jeikeium (D) C. jejuni (D) PF-064 S. epidermidis
(D) DYYGKE 1137 MRSA (M) PF-065 S. epidermidis (D)
LEKNTRDNYFIHAIDRIYINTSKGLFPES 1138 MRSA (R) ELVAWG C. jeikeium (A)
PF-066 MRSA (S) IKGTVKAVDETTVVITVNGHGTELTFE 1139 KPAIKQVDPS PF-067
S. epidermidis (D) DLIVKVHICFVVKTASGYCYLNKREAQ 1140 M. luteus (R)
AAI B. subtilis (C) P. aeruginosa (A) MRSA (M) S. pneumoniae (D) C.
jeikeium (D) C. jejuni (D) PF-068 S. epidermidis (M)
SHLINNFGLSVINPSTPICLNFSPVFNLL 1141 M. luteus (D) TVYGITCN B.
subtilis (A) E. coli (A) MRSA (M) S. pneumoniae (D) E. faecalis (A)
C. jeikeium (R) C. jejuni (D) PF-069 B. subtilis (D)
FDPVPLKKDKSASKHSHKHNH 1142 C. jejuni (R) PF-070 B. subtilis (D)
SMVKSEIVDLLNGEDNDD 1143 PF-071 S. epidermidis (R)
HCVIGNVVDIANLLKRRAVYRDIADVI 1144 M. luteus (R) KMR B. subtilis (D)
C. albicans (B) MRSA (C) S. pneumoniae (A) C. jejuni (A) PF-073 S.
epidermidis (R) CPSVTMDACALLQKFDFCNNISHFRHF 1145 M. luteus (R)
FAIKQPIER MRSA (M) S. pneumoniae (D) C. jeikeium (D) C. jejuni (D)
PF-074 S. epidermidis (D) RDIHPIYFMTKD 1146 MRSA (M) PF-075 S.
epidermidis (D) FVNSLIMKDLSDNDMRFKYEYYNREK 1147 M. luteus (A) DT
MRSA (R) C. jeikeium (D) PF-076 S. epidermidis (S)
LYQYELLSKEEYLKCTLIINQRRNEQK 1148 M. luteus (A) MRSA (R) C. jeikeium
(A) PF-099 S. epidermidis (D) EIIAYLEGRFANA 1149 C. jeikeium (C)
PF-123 S. epidermidis (M) TTRPQVAEDRQLDDALKETFPASDPISP 1150 PF-124
S. epidermidis (C) MADGQIAAIAKLHGVPVATRNIRHFQS 1151 C. jeikeium (R)
FGVELINPWSG PF-125 S. epidermidis (D) YVVGALVILAVAGLIYSMLRKA 1152
M. luteus (C) PF-127 S. epidermidis (M) MLRYLSLFAVGLATGYAWGWIDGLA
1153 M. luteus (A) ASLAV C. jeikeium (A) PF-128 S. epidermidis (D)
GIKVVAARFEEIQFSENFDSIILA 1154 P. aeruginosa (C) PF-129 S.
epidermidis (M) MKLLARDPWVCAWNDIW 1155 C. jeikeium (R) PF-133 C.
jeikeium (R) GDPTAGQKPVECP 1156 PF-135 C. jeikeium (R)
PPARPARIPQTPTLHGASLFRQRS 1157 PF-137 S. epidermidis (D)
VLGKGHDLLDVGKTALKSRVFAWLG 1158 M. luteus (D) GS C. jeikeium (A)
PF-139 S. epidermidis (M) ALSKPAIQARTLCRRQDPP 1159 M. luteus (C) C.
jeikeium (R) PF-140 S. epidermidis (D) FHRRVIRASEWALTTRSFSTPLRSAAR
1160 M. luteus (R) P. aeruginosa (A) C. albicans (B) MRSA (M) S.
pneumoniae (D) C. jeikeium (D) C. jejuni (D) PF-143 P. aeruginosa
(C) LSPRPIIVSRRSRADNNNDWSR 1161 PF-144 S. pneumoniae (H)
RSGQPVGRPSRRAWLR 1162 PF-145 S. epidermidis (D)
GIVLTGRAGLVSGACSMALGVGLG 1163 M. luteus (A) B. subtilis (C) MRSA
(M) S. pneumoniae (R) C. jeikeium (R) C. jejuni (R) PF-148 S.
epidermidis (D) RRGCTERLRRMARRNAWDLYAEHFY 1164 M. luteus (A) B.
subtilis (I) C. albicans (B) MRSA (C) S. pneumoniae (R) C. jeikeium
(H) C. jejuni (H) PF-149 MRSA (H) GKVSVLTRVPRSLGGAPANQ 1165 PF-153
S. epidermidis (M) GILARADCSQIA 1166 C. jeikeium (C) PF-156 MRSA
(H) LITAEQPATAPIAGK 1167 PF-157 S. epidermidis (M)
HTAVVWLAGVSGCVALSHCEPA 1168 PF-164 C. jeikeium (R)
EEVSRALAGIGLGLGCRIG 1169 PF-168 P. aeruginosa (H)
VLPFPAIPLSRRRACVAAPRPRSRQRAS 1170 MRSA (I) PF-171 S. epidermidis
(R) TQVTLCRTW 1171 M. luteus (R) B. subtilis (D) MRSA (M) S.
pneumoniae (D) C. jejuni (R) PF-173 S. epidermidis (A) AGRTAIVQGGG
1172 C. jeikeium (D) PF-175 M. luteus (S) RRRPAGQRPEKASQAMIAA 1173
B. subtilis (D) C. albicans (B) S. pneumoniae (A) C. jejuni (M)
PF-176 S. epidermidis (C) RLTSNQFLTRITPFVFAQH 1174 M. luteus (C) C.
jeikeium (D) PF-178 S. epidermidis (D) EVYSSPTNNVAITVQNN 1175 E.
coli (C) MRSA (M) S. pneumoniae (D) PF-180 S. epidermidis (C)
SGLGDLGFSSEAK 1176 PF-186 S. epidermidis (C) DADKNLSLERDRFAWRVAAP
1177 C. jeikeium (A) PF-188 C. jeikeium (H) ARTFAGRLGTRYFGGLMRSTKA
1178 PF-190 S. epidermidis (C) HFILRKPLLFMIHSLKTGPLDRF 1179 C.
jeikeium (R) PF-191 S. epidermidis (A) QFCNFAWLFLASNNAQVSALA 1180
MRSA (H) C. jeikeium (R) PF-192 S. epidermidis (D) VEEDEAPPPHY 1181
PF-196 S. epidermidis (C) TTARYIRRQCHTSITPLSQG 1182 C. jeikeium (R)
PF-199 S. epidermidis (C) FPAFSFGAIAGSVSVAR 1183 M. luteus (A) C.
jeikeium (R) PF-203 S. epidermidis (A) SWKCHHLAI 1184 C. jeikeium
(R) PF-204 S. epidermidis (C) ALQKQDMNLPSVKNQLVFLKSTG 1185 M.
luteus (C) P. aeruginosa (H) C. jeikeium (D) PF-208 S. epidermidis
(D) DAYHCHLVRSPDAHDLSMRIGFV 1186 C. jeikeium (A) PF-209 S.
epidermidis (C) NYAVVSHT 1187 P. aeruginosa (H) MRSA (I) PF-212 M.
luteus (M) NDSKASN 1188 PF-215 M. luteus (T)
ELKITNYNVNTVLYRYYKWGNDLCE 1189 PF-220 S. pneumoniae (H)
VDPADDGTRHIRPEDGDPIEIDE 1190 PF-224 M. luteus (T) DYFYITLSQKNTF
1191 PF-226 S. epidermidis (C) LMFFSENMDKRDTLSGKFRYFAGSKVI 1192 M.
luteus (T) KLMNWLSENGK PF-233 S. epidermidis (C)
DANAMARTTIAIVYILALIALTISYSL 1193 PF-234 M. luteus (T) RTPYILRS 1194
PF-235 M. luteus (T) GIPFSKPHKRQVNYMKSDVLAYIEQNK 1195 MAHTA PF-249
M. luteus (R) INSRYKISF 1196 PF-250 M. luteus (T)
SEDIFGRLANEKANGLEELRKIRLKQ 1197 PF-255 M. luteus (M)
DHKINESQHNPFRSDSNKQNVDFF 1198 PF-257 M. luteus (R)
VWENRKKYLENEIERHNVFLKLGQEVI 1199 KGLNALASRGR PF-264 M. luteus (H)
MQSLSNRQSLIASYILMGIFLSFGYPPA 1200 SLSKFFCRLSHL PF-270 M. luteus (H)
MYLTPYAWIAVGSIFAFSVTTIKIGDQN 1201 DEKQKSHKNDVHKR PF-271 M. luteus
(T) AAQPQTTSP 1202 PF-273 S. epidermidis (C)
LVGALLIFVALIYMVLKGNADKN 1203 PF-274 M. luteus (M)
SIQEAEKIIKNDPFYIHDVADYDFMWF 1204
EPSKSLEEIKEFV PF-276 M. luteus (M) LDLALSTNSLNLEGFSF 1205 PF-278 S.
epidermidis (I) LSLATFAKIFMTRSNWSLKRFNRL 1206 M. luteus (R) C.
albicans (B) PF-283 S. epidermidis (H) MIRIRSPTKKKLNRNSISDWKSNTSGRF
1207 B. subtilis (H) FY PF-289 B. subtilis (C)
MGRHLWNPSYFVATVSENTEEQIRKY 1208 RKNK PF-290 S. epidermidis (C)
MVHDMTNGTLIIVKH 1209 PF-292 S. epidermidis (C) SFVSTTVRLIFEESKRYKF
1210 B. subtilis (C) PF-293 S. epidermidis (C) YDPLK 1211 PF-294 S.
epidermidis (C) DFLVNFLWFKGELNWGKKRYK 1212 PF-296 S. epidermidis
(C) GAFGMPSIKTNTICGEKGKFISACDAW 1213 B. subtilis (C) LSNLK PF-297
S. epidermidis (C) ISKGIDDIVYVINKILSIGNIFKIIKRK 1214 B. subtilis
(C) PF-301 S. epidermidis (C) GIVLIGLKLIPLLANVLN 1215 B. subtilis
(C) PF-303 B. subtilis (C) EYPWSWISEPWPWDKSFYK 1216 PF-305 B.
subtilis (C) MREWICPSCNETHDRDINASINILKEGL 1217 RLITIQNK PF-306 B.
subtilis (C) GCILPHKKDNYNYIMSKFQDLVKITSKK 1218 PF-307 S.
epidermidis (T) MKRRRCNWCGKLFYLEEKSKEAYCC 1219 B. subtilis (H)
KECRKKAKKVKK C. albicans (B) PF-310 S. epidermidis (C)
GVALIGTILVPLLSGLFG 1220 PF-313 S. epidermidis (C)
YITSHKNARAIIKKFERDEILEEVITHYL 1221 NRK PF-318 S. epidermidis (C)
MGRHLWNPSYFVATVSENTEEQIRKYI 1222 B. subtilis (C) NNQKKQVK PF-319 S.
epidermidis (C) SIGSMIGMYSFRHKTKHIKFTFGIPFILF 1223 B. subtilis (C)
LQFLLVYFYILK PF-322 S. epidermidis (C) GIVLIGLKLIPLLANVLR 1224 B.
subtilis (H) PF-335 S. epidermidis (C) AAYPIEDWSDWYEDFFIMLSNI 1225
B. subtilis (C) PF-339 S. epidermidis (C) KKIDILINKYMYLSK 1226 B.
subtilis (C) PF-342 S. epidermidis (C) AFSGVYKTLIVYTRRK 1227 B.
subtilis (C) PF-344 E. coli (A) DERLPEAKAIRNFNGSVMVLGR 1228 PF-347
S. epidermidis (C) GIFTGVTVVVSLKHC 1229 E. coli (C) MRSA (C) E.
faecalis (C) PF-349 S. epidermidis (C) MPKSCHVPVLCDFFFLVIIKFLALFKTI
1230 E. coli (C) QS MRSA (C) E. faecalis (C) PF-350 S. epidermidis
(C) LAVILRAIVY 1231 E. coli (C) MRSA (C) PF-354 MRSA (H)
FTFSKCRASNGRGFGTLWL 1232 PF-355 S. epidermidis (C) WIAIGLLLYFSLKNQ
1233 E. coli (C) P. aeruginosa (A) MRSA (A) S. pneumoniae (D) E.
faecalis (D) C. jejuni (D) PF-356 S. epidermidis (S)
VSIKIGAIVIGMIGLMELLTE 1234 P. aeruginosa (A) MRSA (C) S. pneumoniae
(R) E. faecalis (R) C. jejuni (D) PF-357 S. epidermidis (M)
MLTIIIGFIFWTMTLMLGYLIGEREGRK 1235 M. luteus (C) HE MRSA (M) S.
pneumoniae (M) PF-360 S. epidermidis (S)
MEQKVKVIFVPRSKPDNQLKTFVSAVL 1236 E. coli (C) FKA MRSA (H) PF-362 E.
coli (C) NIERILKEKVWMIRCVE 1237 MRSA (C) PF-363 S. epidermidis (S)
SMLSVTVMCLMHASVAANQAMEKKV 1238 E. coli (C) MRSA (H) S. pneumoniae
(R) E. faecalis (D) C. jejuni (D) PF-366 S. epidermidis (R)
ALCSVIKAIELGIINVHLQ 1239 E. coli (C) P. aeruginosa (A) MRSA (D) S.
pneumoniae (C) E. faecalis (C) C. jejuni (D) PF-369 S. epidermidis
(S) MSEAVNLLRGARYSQRYAKNQVPYEV 1240 E. coli (R) IIEK MRSA (H) E.
faecalis (C) PF-370 S. epidermidis (C) VIFLHKESGNLKEIFY 1241 E.
coli (R) MRSA (C) PF-373 S. epidermidis (M) HFYLLFER 1242 MRSA (M)
PF-374 S. epidermidis (C) HLFFVKGMFILCQKNQINDE 1243 E. coli (C)
MRSA (M) E. faecalis (C) PF-375 S. epidermidis (C)
MDSAKAQTMRTDWLAVSCLVASAYL 1244 E. coli (C) RSMLA MRSA (C) E.
faecalis (C) PF-376 S. epidermidis (C) MTVFEALMLAIAFATLIVKISNKNDKK
1245 E. coli (C) MRSA (C) E. faecalis (C) PF-378 S. epidermidis (M)
ESAKSNLNFLMQEEWALFLLL 1246 MRSA (M) PF-379 S. epidermidis (C)
VFVVLFIIYLASKLLTKLFPIKK 1247 E. coli (C) MRSA (C) E. faecalis (C)
PF-380 S. epidermidis (C) KKIIPLITLFVVTLVG 1248 E. coli (C) P.
aeruginosa (A) MRSA (D) S. pneumoniae (D) E. faecalis (C) C. jejuni
(D) PF-381 S. epidermidis (C) QGANPCQQVGFTVNDPDCRLAKTV 1249 E. coli
(R) MRSA (C) E. faecalis (C) PF-382 MRSA (M) KYKCSWCKRVYTLRKDHKTAR
1250 PF-383 S. epidermidis (C) WSEIEINTKQSN 1251 E. coli (R) PF-385
E. coli (A) MIKKSILKIKYYVPVLISLTLILSA 1252 PF-386 S. epidermidis
(C) FTLTLITTIVAILNYKDKKK 1253 E. coli (C) MRSA (C) E. faecalis (C)
PF-387 S. epidermidis (C) GAVGIAFFAGNMKQDKRIADRQNKKS 1254 E. coli
(M) EKK MRSA (C) E. faecalis (C) PF-389 S. epidermidis (R)
GLQFKEIAEEFHITTTALQQWHKDNGY 1255 MRSA (C) PIYNKNNRK S. pneumoniae
(D) E. faecalis (R) C. jejuni (R) PF-390 S. epidermidis (D)
VVAYVITQVGAIRF 1256 E. coli (C) MRSA (D) S. pneumoniae (D) E.
faecalis (D) C. jejuni (D) PF-392 MRSA (S) DPAGCNDIVRKYCK 1257 E.
faecalis (A) C. jejuni (A) PF-393 S. epidermidis (R) DLVQSILSEFKKSG
1258 MRSA (C) S. pneumoniae (R) E. faecalis (A) C. jejuni (R)
PF-394 MRSA (C) VLKEECYQKN 1259 E. faecalis (A) PF-395 S.
epidermidis (C) YCVPLGNMGNMNNKIW 1260 E. coli (R) MRSA (C) PF-396
S. epidermidis (S) LIYTILASLGVLTVLQAILGREPKAVKA 1261 E. coli (C)
MRSA (C) E. faecalis (C) PF-397 S. epidermidis (C) VEDLMEDLNA 1262
PF-398 S. epidermidis (C) ILVVLAGILLVVLSYVGISKFKMNC 1263 E. coli
(C) MRSA (C) E. faecalis (C) PF-399 S. epidermidis (C)
FPIISALLGAIICIAIYSFIVNRKA 1264 E. coli (C) MRSA (C) E. faecalis (C)
PF-401 S. epidermidis (C) YWLSRVTTGHSFAFEKPVPLSLTIK 1265 E. coli
(R) MRSA (C) E. faecalis (C) PF-403 S. epidermidis (M)
LLSTEQLLKYYDGETFDGFQLPSNE 1266 E. coli (R) MRSA (M) PF-404 S.
epidermidis (M) VLYFQATVV 1267 MRSA (M) PF-405 MRSA (M)
LVRIEVDDLEEWYERNFI 1268
PF-406 S. epidermidis (C) YLEMNADYLSNMDIFDELWEKYLENNK 1269 MRSA (M)
PF-407 S. epidermidis (M) KPKNKKEKTVISYEKLLSMY 1270 MRSA (C) S.
pneumoniae (R) E. faecalis (R) PF-408 S. epidermidis (M)
YCVPLGNMGNMNNKIW 1271 MRSA (M) PF-410 S. epidermidis (C)
FALELIALCRNLFIVYFP 1272 E. coli (S) MRSA (M) E. faecalis (C) PF-411
S. epidermidis (C) WVAVAILLNIALQTQLT 1273 E. coli (C) P. aeruginosa
(A) MRSA (D) S. pneumoniae (D) E. faecalis (D) C. jejuni (D) PF-413
S. epidermidis (C) TFAGSIKIGVPDLVHVTFNCKR 1274 E. coli (S) MRSA (C)
PF-414 S. pneumoniae (H) LLNKKLE 1275 PF-415 S. pneumoniae (D)
MIDVTIGQKSKTGAFNASYSICFSGENF 1276 SF PF-416 S. pneumoniae (H)
SKAGLYGKIERSDKRE 1277 PF-417 S. epidermidis (M) DSYFRS 1278 MRSA
(M) S. pneumoniae (M) PF-418 S. epidermidis (M)
FFLVHFYIRKRKGKVSIFLNYF 1279 E. coli (C) MRSA (D) S. pneumoniae (D)
E. faecalis (D) C. jejuni (D) PF-419 S. pneumoniae (H)
VVTGKVGSLPQIK 1280 PF-421 S. pneumoniae (H) KHCFEITDKTDVV 1281
PF-422 S. epidermidis (R) MSRKKYENDEKSQKKLKIGRKSDVFY 1282 MRSA (C)
GIID S. pneumoniae (C) E. faecalis (R) C. jejuni (R) PF-423 S.
pneumoniae (H) AGKKERLLSFREQFLNKNKKK 1283 PF-424 S. pneumoniae (H)
IAAFVTSRAFSDTVSPI 1284 PF-425 S. epidermidis (D)
MMELVLKTIIGPIVVGVVLRIVDKWLN 1285 E. coli (C) KDK P. aeruginosa (A)
C. albicans (A) MRSA (D) S. pneumoniae (D) E. faecalis (D) C.
jejuni (D) PF-426 S. epidermidis (D) MLQKYTQMISVTKCIITKNKKTQENVD
1286 E. coli (C) AYN C. albicans (A) MRSA (D) S. pneumoniae (D) E.
faecalis (D) C. jejuni (D) PF-427 E. coli (C) YVLEYHGLRATQDVDAFMAL
1287 MRSA (C) S. pneumoniae (R) E. faecalis (C) PF-428 S.
pneumoniae (H) ENEESIF 1288 PF-429 S. epidermidis (C)
AATLICVGSGIMSSL 1289 MRSA (C) S. pneumoniae (M) E. faecalis (C)
PF-430 S. epidermidis (M) AVVCGYLAYTATS 1290 MRSA (M) S. pneumoniae
(M) PF-431 S. epidermidis (M) VAYAAICWW 1291 MRSA (C) S. pneumoniae
(R) E. faecalis (R) C. jejuni (R) PF-432 S. epidermidis (M)
FNGDSEFFLCIAF 1292 E. coli (R) P. aeruginosa (A) MRSA (M) S.
pneumoniae (D) E. faecalis (D) C. jejuni (D) PF-433 S. pneumoniae
(H) MRKEFHNVLSSGQLLADKRPARDYNRK 1293 PF-434 S. pneumoniae (S)
GQLLADKRPARDYNRK 1294 PF-437 S. pneumoniae (I)
FQKPFTGEEVEDFQDDDEIPTII 1295 PF-439 S. epidermidis (C)
RVLVLKKFHGIMDGNRNVAVFFVGQ 1296 E. coli (R) MRSA (M) S. pneumoniae
(R) E. faecalis (C) PF-440 S. epidermidis (C)
MFIISPDLFNIAVILYILFFIHDILLLILS 1297 E. coli (R) MRSA (C) S.
pneumoniae (R) E. faecalis (C) PF-442 MRSA (M)
MQIFYIKTKIFLSFFLFLLIFSQCFYKIEE 1298 S. pneumoniae (C) PF-443 E.
coli (R) KLLYFFNYFENLQQVHLLVQL 1299 MRSA (C) S. pneumoniae (C)
PF-444 S. epidermidis (C) MAAKLWEEGKMVYASSASMTKRLKL 1300 E. coli
(R) AMSKV MRSA (C) S. pneumoniae (R) E. faecalis (C) PF-445 S.
pneumoniae (M) ASMTKRLKLAMSKV 1301 PF-446 S. pneumoniae (H) SGNEKV
1302 PF-447 S. epidermidis (C) IDKSRNKDQFSHIFGLYNICSG 1303 MRSA (C)
S. pneumoniae (C) E. faecalis (C) PF-448 S. pneumoniae (I)
SLQSQLGPCLHDQRH 1304 PF-449 S. pneumoniae (H) MPTTKSKQKGWTNTKKASNTQ
1305 PF-450 MRSA (C) HRNLIILQRTIFI 1306 S. pneumoniae (C) E.
faecalis (C) PF-451 S. epidermidis (C) MVNYIIGSYMLYREQNNNEALRKFDIT
1307 E. coli (R) LAM MRSA (C) S. pneumoniae (C) E. faecalis (C)
PF-452 S. epidermidis (C) MNNWIKVAQISVTVINEVIDIMKEKQN 1308 E. coli
(C) GGK MRSA (C) S. pneumoniae (R) E. faecalis (C) PF-453 S.
epidermidis (C) IIQDIAHAFGY 1309 E. coli (C) MRSA (C) S. pneumoniae
(C) PF-454 S. epidermidis (C) MSVFVPVTNIFMFIMSPIFNVNLLHFKV 1310 E.
coli (R) YI P. aeruginosa (H) MRSA (C) S. pneumoniae (R) E.
faecalis (C) PF-455 S. pneumoniae (A) MARNDDDIKKIKGTLGQSPEVYGERK
1311 LPYT PF-456 E. faecalis (A) TCVKPRTIN 1312 C. jejuni (A)
PF-457 S. pneumoniae (M) INKYHHIA 1313 PF-458 P. aeruginosa (H)
ISLIIFIMLFVVALFKCITNYKHQS 1314 MRSA (M) S. pneumoniae (M) PF-459 S.
pneumoniae (H) EKRMSFNENQSHRPLL 1315 PF-460 S. epidermidis (C)
MEHVLPFQNTPPNIVIIYKDFTHLKSITFS 1316 E. coli (H) MRSA (C) S.
pneumoniae (R) E. faecalis (C) PF-461 MRSA (R)
MTLAIKNCSVTKCLGFGDFVNDDSDS 1317 S. pneumoniae (R) YFDA E. faecalis
(A) PF-462 S. pneumoniae (H) KNKTDTL 1318 PF-464 S. pneumoniae (S)
VDMVNRFLGN 1319 PF-465 S. pneumoniae (H) KPVGKALEEIADGKIEPVVPKEYLG
1320 PF-466 S. pneumoniae (H) VRKSDQ 1321 PF-467 S. pneumoniae (H)
YYKDYFKEI 1322 PF-468 S. pneumoniae (H) EDNKDKKDKKDK 1323 PF-469 S.
epidermidis (D) YKVNYNNIDNHFNTLRH 1324 E. coli (C) MRSA (D) S.
pneumoniae (D) E. faecalis (D) C. jejuni (D) PF-470 E. faecalis (A)
PYSDSYATRPHWEQHRAR 1325 C. jejuni (A) PF-471 S. epidermidis (C)
MVGKIRGVTPRNDLLNANITGQLNLN 1326 E. coli (C) YRLI P. aeruginosa (A)
MRSA (D) S. pneumoniae (D) E. faecalis (C) C. jejuni (D) PF-472
MRSA (C) MHISHLLDEVEQTEREKAVNVLENMN 1327 S. pneumoniae (R) GNVI E.
faecalis (A) C. jejuni (R) PF-473 S. epidermidis (R)
MAADIISTIGDLVKWIIDTVNKFKK 1328 E. coli (C) MRSA (C) S. pneumoniae
(H) E. faecalis (R) C. jejuni (R) PF-474 S. epidermidis (C)
MHRNLVLVKMEPIPHIMIIANQIGIIIEKA 1329 E. coli (C) P. aeruginosa (A)
C. albicans (B) MRSA (D)
S. pneumoniae (D) E. faecalis (C) C. jejuni (D) PF-475 S.
epidermidis (M) MREKVRFTQAFKLFWTNYFNFKGRSR 1330 C. albicans (B)
RSEY MRSA (S) S. pneumoniae (R) E. faecalis (R) C. jejuni (R)
PF-476 S. pneumoniae (H) WADAQYKLCENCSE 1331 PF-477 S. pneumoniae
(H) HKNKLNIPHIKS 1332 PF-478 S. epidermidis (C)
HLFILKSHLKPFPPFRYTYD 1333 E. coli (C) MRSA (H) S. pneumoniae (C)
PF-479 S. pneumoniae (C) AYILKRREEKNK 1334 PF-480 S. epidermidis
(C) MVEILVNTAISVYIVALYTQWLSTRDN 1335 E. coli (R) LKA MRSA (C) S.
pneumoniae (R) E. faecalis (C) PF-482 S. pneumoniae (S)
LVGYVRTSGTVRSYKIN 1336 PF-484 E. faecalis (A) HKKDIRKQVFKN 1337
PF-485 S. pneumoniae (A) KNSMSRSIALID 1338 PF-511 S. pneumoniae (H)
VMQSLYVKPPLILVTKLAQQN 1339 PF-512 S. pneumoniae (H)
SFMPEIQKNTIPTQMK 1340 PF-513 S. pneumoniae (M) SNGVGLGVGIGSGIRF-NH2
1341 PF-514 S. epidermidis (C) QRFYKLFYHIDLTNEQALKLFQVK 1342 E.
coli (R) S. pneumoniae (M) E. faecalis (C) PF-515 S. pneumoniae (H)
DKSTQDKDIKQAKLLAQELGL-NH2 1343 PF-516 S. pneumoniae (H)
ASKQASKQASKQASKQ 1344 PF-517 S. pneumoniae (M) VKPTMTASLISTVC 1345
PF-518 S. epidermidis (C) SFYSKYSRYIDNLAGAIFLFF 1346 E. coli (R)
MRSA (C) S. pneumoniae (M) E. faecalis (C) PF-519 E. coli (R)
YLVYSGVLATAAAF-NH2 1347 MRSA (C) S. pneumoniae (S) E. faecalis (C)
PF-520 S. pneumoniae (M) LGLTAGVAYAAQPTNQPTNQPTNQPT 1348
NQPTNQPTNQPRW-NH2 PF-521 S. pneumoniae (H) CGKLLEQKNFFLKTR 1349
PF-522 S. pneumoniae (H) FELVDWLETNLGKILKSKSA-NH2 1350 PF-524 E.
coli (M) PDAPRTCYHKPILAALSRIVVTDR 1351 MRSA (C) S. pneumoniae (M)
E. faecalis (C) PF-525 S. pneumoniae (H) KFSDQIDKGQDALKDKLGDL 1352
PF-526 S. epidermidis (C) VLLLFIFQPFQKQLL-NH2 1353 E. coli (R) C.
albicans (C) MRSA (C) S. pneumoniae (R) PF-527 S. epidermidis (M)
GSVIKKRRKRMAKKKHRKLLKKTRIQ 1354 M. luteus (S) RRRAGK B. subtilis
(I) P. aeruginosa (I) C. albicans (B) MRSA (I) S. pneumoniae (H) C.
jeikeium (I) C. jejuni (M) PF-528 S. epidermidis (H)
LVDVVVLIRRHLPKSCS-NH2 1355 E. coli (H) C. albicans (C) MRSA (H) S.
pneumoniae (R) PF-529 S. pneumoniae (H) LSEMERRRLRKRA-NH2 1356
PF-530 S. epidermidis (H) SKFKVLRKIIIKEYKGELMLSIQKQR 1357 E. coli
(R) MRSA (C) S. pneumoniae (R) E. faecalis (C) PF-531 S.
epidermidis (I) YIQFHLNQQPRPKVKKIKIFL-NH2 1358 E. coli (M) P.
aeruginosa (I) S. pneumoniae (C) PF-532 E. coli (C)
KFIYKYKLSFIIYKILIQTLTMELNK 1359 MRSA (C) S. pneumoniae (C) E.
faecalis (C) PF-533 S. epidermidis (H) KTPNDKIHKTIIIKHIIL 1360 E.
coli (R) MRSA (H) S. pneumoniae (C) E. faecalis (C) PF-534 S.
epidermidis (C) KYFHLFYHNIIHYSKQHLSLKVDFKN- 1361 E. coli (R) NH2
MRSA (C) S. pneumoniae (R) E. faecalis (C) PF-535 P. aeruginosa (H)
NIKTRKRALKIIKQHQRSK 1362 S. pneumoniae (H) PF-536 S. epidermidis
(C) MEPIPHIMIIANQIGIIIEKA 1363 E. coli (R) P. aeruginosa (H) MRSA
(C) S. pneumoniae (M) E. faecalis (C) PF-537 S. pneumoniae (C)
LANDYYKKTKKSW 1364 PF-538 S. pneumoniae (H)
KNKKQTDILEKVKEILDKKKKTKSVG 1365 QKLY PF-539 MRSA (H)
SIILTKKKRRKIPLSIDSQIYKYTFKQ 1366 S. pneumoniae (A) PF-540 S.
epidermidis (H) KSILILIKVIFIGQTTIIL 1367 E. coli (R) MRSA (H) S.
pneumoniae (R) PF-541 E. coli (H) RRNLNSPNIKTRKRALKIIKQHQRSK 1368
S. pneumoniae (H) PF-542 S. pneumoniae (H) KKDNPSLNDQDKNAVLNLLALAK
1369 PF-543 S. mutans (S) NILFGIIGFVVAMTAAVIVTAISIAK 1370 S.
epidermidis (D) M. luteus (C) E. coli (C) MRSA (D) S. pneumoniae
(D) PF-544 S. epidermidis (D) FGEKQMRSWWKVHWFHP 1371 MRSA (D) S.
pneumoniae (M) E. faecalis (R) PF-545 B. subtilis (I)
RESKLIAMADMIRRRI-NH2 1372 C. albicans (B) E. faecalis (H) C.
jeikeium (H) PF-546 S. epidermidis (D) PIIAPTIKTQIQ 1373 E. coli
(R) MRSA (D) S. pneumoniae (D) E. faecalis (D) C. jeikeium (D)
PF-547 S. epidermidis (R) WSRVPGHSDTGWKVWHRW-NH2 1374 B. subtilis
(I) MRSA (M) E. faecalis (R) PF-548 S. epidermidis (M)
ARPIADLIHFNSTTVTASGDVYYGPG 1375 M. luteus (A) B. subtilis (C) MRSA
(M) S. pneumoniae (D) C. jeikeium (R) C. jejuni (D) PF-549 B.
subtilis (D) TGIGPIARPIEHGLDS 1376 MRSA (C) PF-550 B. subtilis (D)
STENGWQEFESYADVGVDPRRYVPL 1377 PF-551 MRSA (C)
QVKEKRREIELQFRDAEKKLEASVQAE 1378 PF-552 B. subtilis (D)
ELDKADAALGPAKNLAPLDVINRS 1379 PF-553 B. subtilis (D)
LTIVGNALQQKNQKLLLNQKKITSLG 1380 MRSA (M) S. pneumoniae (R) C.
jeikeium (R) PF-554 B. subtilis (D) AKNFLTRTAEEIGEQAVREGNINGP 1381
PF-555 MRSA (M) EAYMRFLDREMEGLTAAYNVKLFTEA 1382 S. pneumoniae (R)
IS C. jejuni (R) PF-556 S. epidermidis (A) SLQIRMNTLTAAKASIEAA 1383
M. luteus (A) B. subtilis (C) MRSA (M) S. pneumoniae (D) E.
faecalis (A) C. jeikeium (D) C. jejuni (R) PF-557 B. subtilis (D)
AANKAREQAAAEAKRKAEEQAR 1384 PF-558 S. epidermidis (M) ADAPPPLIVRYS
1385 B. subtilis (D) MRSA (C) S. pneumoniae (R) C. jejuni (H)
PF-559 B. subtilis (C) SRPGKPGGVSIDVSRDRQDILSNYP 1386 C. jejuni (A)
PF-560 B. subtilis (D) FGNPFRGFTLAMEADFKKRK 1387 MRSA (C) S.
pneumoniae (R) C. jejuni (A) PF-561 B. subtilis (D)
ESLEADVQAELDTEAAKYPALPASF 1388 MRSA (M) PF-562 S. epidermidis (A)
TPEQWLERSTVVVTGLLNRK 1389 M. luteus (R) MRSA (M) S. pneumoniae (D)
C. jejuni (R) PF-563 B. subtilis (D) RPELDNELDVVQNSASLDKLQASYN 1390
S. pneumoniae (H) C. jejuni (H)
PF-564 B. subtilis (D) TIILNDQINSLQERLNKLNAETDRR 1391 MRSA (C) C.
jeikeium (R) C. jejuni (R) PF-565 B. subtilis (D)
RAEAEAQRQAEADAKRKAEEAARL 1392 MRSA (C) PF-566 M. luteus (D)
EAQQVTQQLGADFNAITTPTATKV 1393 B. subtilis (C) MRSA (M) S.
pneumoniae (D) C. jeikeium (C) C. jejuni (D) PF-567 M. luteus (C)
QQRVKAVDASLSQVSTQVSGAVASA 1394 MRSA (D) S. pneumoniae (D) C.
jeikeium (C) C. jejuni (D) PF-569 B. subtilis (D)
KSKISEYTEKEFLEFVEDIYTNNK 1395 PF-571 B. subtilis (D)
SDLLYYPNENREDSPAGVVKEVKE 1396 PF-572 B. subtilis (D) WRASKGLPGFKAG
1397 S. pneumoniae (R) PF-573 S. pneumoniae (C)
EKKLIVKLIDSIGKSHEEIVGAG 1398 PF-574 B. subtilis (D)
LVKSGKLESPYEHSEHLTLSQEKGLE 1399 PF-575 P. aeruginosa (A)
LNFRAENKILEKIHISLIDTVEGSA 1400 S. pneumoniae (A) C. jeikeium (A) C.
jejuni (R) PF-576 S. epidermidis (A) AYSGELPEPLVRKMSKEQVRSVMGK 1401
E. coli (A) MRSA (R) S. pneumoniae (C) C. jejuni (C) PF-577 S.
epidermidis (A) PFETRESFRVPVIGILGGWDYFMHP 1402 E. coli (A) P.
aeruginosa (A) MRSA (M) S. pneumoniae (R) E. faecalis (A) C. jejuni
(R) PF-578 S. mutans (D) QKANLRIGFTYTSDSNVCNLTFALLGSK 1403 S.
epidermidis (D) M. luteus (C) P. mirabilis (C) E. coli (C) MRSA (C)
S. pneumoniae (D) PF-580 S. epidermidis (M)
EILNNNQVIKELTMKYKTQFESNLGG 1404 M. luteus (C) WTARARR MRSA (M) S.
pneumoniae (C) PF-581 MRSA (A) WTARARR 1405 S. pneumoniae (A) E.
faecalis (A) C. jejuni (A) PF-582 E. faecalis (A)
NLKTIEKECPFCNNKMDIKLKD 1406 PF-583 S. mutans (F)
KFQGEFTNIGQSYIVSASHMSTSLNTGK 1407 S. epidermidis (I) MRSA (I) S.
pneumoniae (D) PF-584 S. epidermidis (C) SYIKNLSNQKFLIAF 1408 E.
coli (C) MRSA (D) S. pneumoniae (D) E. faecalis (D) C. jejuni (D)
PF-585 S. epidermidis (S) DYNHLLNVVQDWVNTN 1409 MRSA (S) S.
pneumoniae (R) E. faecalis (A) C. jejuni (R) PF-586 S. epidermidis
(C) FFNQANYFFKEF 1410 E. coli (C) MRSA (D) S. pneumoniae (D) E.
faecalis (D) C. jejuni (D) PF-587 S. pneumoniae (C)
ASGKYQSYLLNVYVDSKKDRLDIFDK 1411 LKAKAKFVL PF-588 E. faecalis (A)
ESVEAIKAKAIK 1412 PF-589 MRSA (M) APLRIDEIRNSNVIDEVLDCAPKKQEHF 1413
S. pneumoniae (C) FVVPKIIE PF-590 C. jejuni (R) YYQAKLFPLL 1414
PF-591 S. pneumoniae (R) DLLKSLLGQDGAKNDEIIEFIKIIMEK 1415 E.
faecalis (A) C. jejuni (C) PF-592 S. epidermidis (M)
IMKNYKYFKLFIVKYALF 1416 E. coli (C) MRSA (D) S. pneumoniae (D) E.
faecalis (D) C. jejuni (S) PF-593 E. faecalis (A)
MEISTLKKEKLHVKDELSQYLANYKK 1417 PF-594 E. faecalis (C) IVSAIV 1418
PF-595 S. epidermidis (C) LQNKIYELLYIKERSKLCS 1419 E. coli (C) MRSA
(D) S. pneumoniae (R) E. faecalis (D) C. jejuni (D) PF-596 S.
epidermidis (D) SKMWDKILTILILILELIRELIKL 1420 E. coli (C) MRSA (D)
S. pneumoniae (D) E. faecalis (D) C. jejuni (D) PF-597 E. faecalis
(A) DEIKVSDEEIEKFIKENNL 1421 PF-598 S. epidermidis (R)
MKFMLEVRNKAISAYKEITRTQI 1422 E. coli (C) MRSA (D) S. pneumoniae (R)
E. faecalis (R) C. jejuni (R) PF-599 S. epidermidis (M) LFEIFKPKH
1423 MRSA (C) S. pneumoniae (R) E. faecalis (A) C. jejuni (R)
PF-600 S. mutans (S) TKKIELKRFVDAFVKKSYENYILEREL 1424 S.
epidermidis (C) KKLIKAINEELPTK M. luteus (C) E. coli (H) MRSA (M)
S. pneumoniae (R) PF-601 E. faecalis (A) YRVTVKALE 1425 C. jejuni
(A) PF-602 E. faecalis (A) LEKEKKEYIEKLFKTK 1426 PF-603 S.
epidermidis (D) IDKLKKMNLQKLSYEVRISQDGKSIYA 1427 M. luteus (A) RIK
E. coli (M) MRSA (M) S. pneumoniae (C) PF-604 E. faecalis (A)
LMEQVEV 1428 PF-605 S. epidermidis (R) HYRWNTQWWKY 1429 E. coli (C)
P. aeruginosa (A) C. albicans (B) MRSA (C) S. pneumoniae (D) E.
faecalis (R) C. jejuni (R) PF-606 S. mutans (I)
FESKILNASKELDKEKKVNTALSFNSH 1430 S. epidermidis (I) QDFAKAYQNGKI C.
albicans (B) MRSA (I) S. pneumoniae (H) PF-607 S. epidermidis (M)
YIESDPRKFDYIFGAIRDH 1431 MRSA (S) S. pneumoniae (R) E. faecalis (A)
C. jejuni (R) PF-609 MRSA (C) TEIKLDNNEYLVLNLDDILGILK 1432 S.
pneumoniae (R) E. faecalis (A) C. jejuni (R) PF-610 S. epidermidis
(C) VFLKLKTSKIDLASIIFYP 1433 E. coli (C) MRSA (D) S. pneumoniae (D)
E. faecalis (D) C. jejuni (D) PF-612 S. mutans (F)
GTTLKYGLERQLKIDIHPEITIINLNGGA 1434 S. epidermidis (C) DEFAKL M.
luteus (A) P. mirabilis (C) E. coli (C) MRSA (C) S. pneumoniae (C)
PF-613 S. epidermidis (R) ADEFAKL 1435 MRSA (C) E. faecalis (A)
PF-614 S. epidermidis (M) GLDIYA 1436 S. pneumoniae (R) E. faecalis
(A) C. jejuni (R) PF-615 S. epidermidis (D)
FLNRFIFYIFTVKTKSALIKNLFLD 1437 E. coli (C) MRSA (D) S. pneumoniae
(D) E. faecalis (D) C. jejuni (D) PF-616 S. epidermidis (R)
IVFVVTKEKK 1438 E. faecalis (A) PF-617 C. albicans (H) PMNAAEPE
1439 S. pneumoniae (I) E. faecalis (H) PF-618 S. pneumoniae (I)
KLNTLNKKDNPSLNDQDKNAVLNLLA 1440 E. faecalis (H) LAK PF-619 S.
epidermidis (M) WSRVPGHSDTGWKVWHRW 1441 E. coli (C) MRSA (M) S.
pneumoniae (C) PF-621 S. pneumoniae (I) PPSSFLV 1442 E. faecalis
(H) PF-622 S. epidermidis (D) TREDVFSVRLINNIVNKQA 1443 MRSA (D) S.
pneumoniae (M) E. faecalis (D) C. jeikeium (D)
PF-623 S. epidermidis (M) VLFAVYLGALDWLFSWLTQKM 1444 MRSA (D) S.
pneumoniae (D) E. faecalis (D) C. jeikeium (R) PF-624 S. mutans (D)
VFLLDSYCFVKINL 1445 S. epidermidis (D) M. luteus (C) P. mirabilis
(C) E. coli (C) MRSA (C) S. pneumoniae (D) PF-625 S. pneumoniae (H)
SDSTNNARTRKKARDVTTKDIDK 1446 PF-626 S. pneumoniae (H) KYDFDDFEPEEA
1447 PF-627 S. epidermidis (H) INDLLSYFTLHEK 1448 C. albicans (B)
MRSA (R) S. pneumoniae (I) E. faecalis (H) PF-629 S. epidermidis
(C) GLAAIATVFALY 1449 MRSA (D) S. pneumoniae (M) E. faecalis (R) C.
jeikeium (R) PF-630 MRSA (M) IPATPIIHS 1450 PF-631 S. pneumoniae
(I) LIIYFSKTGNTARATRQI 1451 E. faecalis (H) PF-632 S. epidermidis
(D) TTIQGVASLEKHGFRYTIIYPTRI 1452 B. subtilis (H) C. albicans (B)
MRSA (D) S. pneumoniae (M) E. faecalis (D) C. jeikeium (D) PF-634
S. mutans (D) MPKARPVNHNKKKSKITIKSNFTLFYM 1453 S. epidermidis (D)
FNP M. luteus (C) P. mirabilis (C) E. coli (C) MRSA (D) S.
pneumoniae (D) PF-635 S. epidermidis (M) MNAHGHSLIFQKMIVHAFAFFSKQKN
1454 C. albicans (B) YLYF MRSA (D) S. pneumoniae (D) E. faecalis
(D) C. jeikeium (D) PF-636 B. subtilis (H) LVRLA 1455 C. albicans
(B) S. pneumoniae (H) E. faecalis (H) PF-637 S. epidermidis (M)
SRIKQDARSVRKYDRIGIFFYSFKSA 1456 MRSA (M) S. pneumoniae (M) E.
faecalis (D) C. jeikeium (D) PF-638 S. epidermidis (R) TFILPK 1457
MRSA (M) S. pneumoniae (I) E. faecalis (H) PF-639 C. albicans (B)
QATQIKSWIDRLLVSED 1458 MRSA (R) S. pneumoniae (I) E. faecalis (H)
PF-640 C. albicans (B) MGDINRNF 1459 S. pneumoniae (I) E. faecalis
(H) PF-642 MRSA (M) FTTPMIGIPAGLLGGSYYLKRREEKGK 1460 PF-643 MRSA
(C) VRCRL 1461 S. pneumoniae (R) E. faecalis (R) PF-644 S.
pneumoniae (H) TSGLIIGENGLNGL 1462 PF-645 C. albicans (B) SNSVQQG
1463 S. pneumoniae (I) PF-646 C. albicans (B) APASPGRRPG 1464 S.
pneumoniae (H) PF-647 C. albicans (B) GTFLGQKCAAATAS 1465 S.
pneumoniae (R) PF-649 E. faecalis (R) CPRYPFVDVGPAGPWRARWRVGS 1466
PF-651 S. pneumoniae (H) PRWPTGAGRHR 1467 PF-652 S. pneumoniae (A)
FLAPARPDLQAQRQALAQ 1468 PF-653 S. pneumoniae (H) QSVHPLPAETPVADVI
1469 PF-654 C. albicans (B) LSGRLAGRR 1470 MRSA (R) S. pneumoniae
(A) PF-655 S. epidermidis (R) DAPCFDDQFGDLKCQMC 1471 B. subtilis
(H) MRSA (M) S. pneumoniae (H) PF-656 MRSA (R) RGMFVPFHDVDCVQ 1472
PF-657 S. epidermidis (C) YVANYTITQFGRDFDDRLAVAIHFA 1473 MRSA (D)
S. pneumoniae (H) E. faecalis (D) C. jeikeium (D) PF-658 MRSA (R)
PTTPPPTTPPEIPTGGTVIST 1474 S. pneumoniae (H) PF-659 S. epidermidis
(M) TVIST 1475 B. subtilis (H) MRSA (R) S. pneumoniae (C) PF-660 S.
pneumoniae (H) TDPQATAAPRRRTSPR 1476 PF-661 MRSA (R)
PDEDIRRRAILPPAGPCRPMSPE 1477 PF-662 S. pneumoniae (A)
GKQSRAHGPVASRREFRRKSG 1478 PF-663 S. pneumoniae (A) ATLIPRKA 1479
PF-664 S. epidermidis (M) DQLCVEYPARVSTG 1480 MRSA (R) S.
pneumoniae (M) E. faecalis (R) PF-665 S. pneumoniae (H)
VLRVATAVGEVPTGL 1481 PF-666 S. pneumoniae (A) PNRRSRPR 1482 PF-667
S. epidermidis (R) PAHQRLRIDQRLVADRDMVQDYES 1483 MRSA (R) S.
pneumoniae (R) E. faecalis (R) PF-668 S. epidermidis (M)
TNAESMALAFRGRVHMSVNIAGLT 1484 B. subtilis (A) C. albicans (A) MRSA
(R) S. pneumoniae (M) E. faecalis (D) C. jeikeium (D) PF-670 B.
subtilis (H) TVIVAPMHSGV 1485 S. pneumoniae (H) PF-672 S.
epidermidis (I) MRFGSLALVAYDSAIKHSWPRPSSVRR 1486 B. subtilis (I)
LRM C. albicans (I) MRSA (I) S. pneumoniae (I) E. faecalis (I) C.
jeikeium (R) PF-675 S. pneumoniae (C) EIIPISPTRRCEMHTMSSAEYRGL 1487
E. faecalis (R) PF-677 S. epidermidis (R) TCRGAGMH 1488 MRSA (D) S.
pneumoniae (D) E. faecalis (R) PF-680 MRSA (R) ADPHPTTGI 1489
PF-681 S. epidermidis (M) TALTTVGVSGARLITYCVGVEDI 1490 MRSA (M) S.
pneumoniae (M) E. faecalis (R) C. jeikeium (R) PF-682 S. pneumoniae
(A) RRGKSEQGLSRR 1491 PF-683 S. epidermidis (R) LWPVA 1492 MRSA (R)
S. pneumoniae (H) PF-684 C. albicans (B) RKLSLASGFALWRRSLV 1493 S.
pneumoniae (C) E. faecalis (A) PF-685 S. epidermidis (M) PTLWLACL
1494 MRSA (M) S. pneumoniae (M) E. faecalis (R) C. jeikeium (R)
PF-686 S. epidermidis (H) LAVLMGYIGYRGWSGKRHINRQ 1495 B. subtilis
(I) C. albicans (B) MRSA (M) S. pneumoniae (A) E. faecalis (R)
PF-687 S. pneumoniae (A) AKRVLSLAVAPHRRQPVQGT 1496 PF-688 S.
pneumoniae (A) ARNHAVIPAG 1497 PF-690 S. epidermidis (R)
MIPLAGDPVSSHRTVEFGVLGTYLVSG 1498 MRSA (R) GSL S. pneumoniae (M) E.
faecalis (R) PF-691 S. pneumoniae (R) HRTVEFGVLGTYLVSGGSL 1499
PF-692 MRSA (R) GVAREDPLEPDPLAPIIDDSR 1500 PF-693 S. pneumoniae (A)
PDPAR 1501 PF-694 MRSA (R) DLIRPLYSMSAPSVA 1502 S. pneumoniae (A)
PF-695 MRSA (R) ALSVMLGNIPLVVPNANQL 1503 S. pneumoniae (C) E.
faecalis (R) PF-696 S. pneumoniae (H) IRSGISAAYARPLR 1504 PF-697 C.
albicans (H) RADARAK 1505 S. pneumoniae (H) PF-698 C. albicans (H)
SSGRAGVKCRRPTGR 1506 S. pneumoniae (A) E. faecalis (A) PF-699 S.
pneumoniae (A) GRAGVKCRRPTGR 1507 PF-700 S. pneumoniae (C) LNWPFTGR
1508 PF-702 S. pneumoniae (H) LSGRLAGRR 1509 PF-704 S. pneumoniae
(C) APAARAAL 1510
PF-737 S. pneumoniae (D) KSSGSSASASSTAGGSSSK 1511 PF-738 MRSA (M)
KSGATSAASGAKSGASS 1512 PF-741 S. mutans (D) AKREDTVAAQIGANILNLIQ
1513 S. epidermidis (C) M. luteus (C) P. mirabilis (C) E. coli (C)
MRSA (C) S. pneumoniae (D) PF-744 S. pneumoniae (H)
LGVGTFVGKVLIKNQQKQKSKKKAQ 1514 PF-745 S. mutans (D)
ANSQNSLFSNRSSFKSIFDKKSNITTNA 1515 M. luteus (C) TTPNSNIIIN MRSA (C)
S. pneumoniae (C) PF-746 S. mutans (D) FLGNSQYFTRK 1516 S.
epidermidis (C) M. luteus (C) E. coli (C) P. aeruginosa (A) MRSA
(C) S. pneumoniae (C) PF-748 S. pneumoniae (H)
FQGFFDVAVNKWWEEHNKAKLWKN 1517 VKGKFLEGEGEEEDDE PF-749 S. pneumoniae
(H) GVNKWWEEHNKAKLWKNVKGKFLE 1518 GEGEEEDDE PF-752 S. pneumoniae
(C) LHVIRPRPELSELKFPITKILKVNKQGL 1519 KK PF-756 S. pneumoniae (A)
DALLRLA 1520 PF-757 S. pneumoniae (H) PQAISSVQQNA 1521 PF-760 S.
epidermidis (M) DHITLDDYEIHDGFNFELYYG 1522 MRSA (M) S. pneumoniae
(C) PF-761 S. mutans (D) SKFELVNYASGCSCGADCKCASETECK 1523 S.
epidermidis (C) CASKK M. luteus (C) E. coli (C) P. aeruginosa (C)
MRSA (D) S. pneumoniae (C) PF-762 S. pneumoniae (H)
PAPAPSAPAPAPEQPEQPA 1524 PF-763 S. epidermidis (M)
GIWMARNYFHRSSIRKVYVESDKEYE 1525 M. luteus (C) RVHPMQKIQYEGNYKSQ
MRSA (D) S. pneumoniae (C) PF-764 MRSA (D) GYFEPGKRD 1526 S.
pneumoniae (H) PF-770 S. mutans (D) GVGIGFIMMGVVGYAVKLVHIPIRYLIV
1527 S. epidermidis (D) M. luteus (C) P. mirabilis (C) E. coli (C)
MRSA (D) S. pneumoniae (C) PF-776 S. mutans (D)
VSILLYLSATIILPNVLRLLVARAIIVRV 1528 S. epidermidis (D) M. luteus (C)
E. coli (C) MRSA (D) S. pneumoniae (C) PF-C052 P. gingivalis (H)
SRFRNGV 1529 PF-C055 F. nucleatum (T) YNLSIYIYFLHTITIAGLITLPFII
1530 S. mutans (I) PF-C057 S. mutans (I) YFWWYWVQDCIPYKNNEVWLELSNN
1531 MK PF-C058 S. mutans (F) FETGFGDGYYMSLWGLNEKDEVCKV 1532
VIPFINPELID PF-C061 F. nucleatum (T) TLNYKKMFFSVIFLLGLNYLICNSPLFF
1533 S. mutans (F) KQIEF PF-C062 F. nucleatum (T)
PLARATEVVATLFIICSLLLYLTR 1534 S. mutans (I) PF-C064 F. nucleatum
(T) DEEALEMGANLYAQFAIDFLNSKK 1535 PF-C065 F. nucleatum (T)
DEERYSDSYFLKEKVFYLILALFLILFH 1536 QKYLYFLEIITI PF-C069 F. nucleatum
(T) NALMLREMQLAKNIKVEVTDVLSNKK 1537 YC PF-C071 F. nucleatum (T)
QVIVKIL 1538 PF-C072 F. nucleatum (T) KKMFSLIRKVNWIFFILFIVLDLTNVFP
1539 P. gingivalis (T) LIRTILFAILSRQ S. mutans (F) PF-C075 F.
nucleatum (T) KALVISVFAIVFSIIFVKFFYWRDKK 1540 P. gingivalis (R) S.
mutans (F) PF-C084 F. nucleatum (T) FFSVIFLFGLNYLICNSPLFNILR 1541
P. gingivalis (R) S. mutans (F) PF-C085 S. mutans (F)
KKFKIFVIINWFYHKYIILNFEENF 1542 PF-C086 F. nucleatum (T)
ELFFTILSDCNELFLLHLLQQPLFYIKK 1543 GK PF-C088 F. nucleatum (H)
DIANNILNSVSERLIIA 1544 P. gingivalis (R) S. mutans (I) PF-C089 P.
gingivalis (R) MPKRHYYKLEAKALQFGLPFAYSPIQL 1545 LK PF-C091 F.
nucleatum (T) ASNTPRFVRLTLFNFYSKIWNVTHLFLF 1546 NNL PF-C095 F.
nucleatum (T) LLALNMNEDTYYFELFFIFDNQNKKW 1547 LIFDLKERG PF-C098 F.
nucleatum (T) PETKGKVSAFVFGIVVANVIAVVYILY 1548 S. mutans (F)
MLREIGIIQ PF-C120 F. nucleatum (T) ASLSTMTFKVMELKELIILLCGLTMLMI
1549 QTEFV PF-C131 F. nucleatum (T) QWIVAKREIRMHIYCHISVIHVIIFFG
1550 S. mutans (F) PF-C135 F. nucleatum (C)
KNTHAYLRVLRLSSLILSYQASVYPLF 1551 S. mutans (F) AYLCQQKDY PF-C136 F.
nucleatum (C) LILSYQASVYPLFAYLCQQKDY 1552 P. gingivalis (R) PF-C137
F. nucleatum (T) QRMYWFKRGFETGDFSAGDTFAELK 1553 PF-C139 S. mutans
(F) LLASHPERLSLGVFFVYRVLHLLLENT 1554 PF-C142 S. mutans (I)
DFPPLSFFRRRFHAYTAPIDNFFGANPF 1555 PF-C143 F. nucleatum (C)
VVFGGGDRLV 1556 PF-C145 F. nucleatum (C) YGKESDP 1557 S. mutans (I)
PF-C180 P. gingivalis (R) TVEELDKAFTWGAAAALAIGVIAINVG 1558 S.
mutans (S) LAAGYCYNNNDVF PF-C181 F. nucleatum (T)
KMRAGQVVFIYKLILVLLFYVLQKLFD 1559 LKKGCF PF-C194 F. nucleatum (T)
NTNDLLQAFELMGLGMAGVFIVLGILY 1560 P. gingivalis (T) IVAELLIKIFPVNN
S. mutans (F) PF-C214 F. nucleatum (T) GGHKQLVIEPLVSQ 1561 PF-C281
S. mutans (F) KKEKLLTAIRLQHRAEIRGYFTIFFLFFRI 1562 PF-C290 S. mutans
(F) GNVHPESDFHNLIQFIKTFLYFTIFFKYFL 1563 PF-C291 F. nucleatum (T)
HPFLTGTGCPLFLIFRLFFVKAYFSFTVF 1564 S. mutans (F) PF-C293 F.
nucleatum (T) IIIILPKIYLVCKTV 1565 P. gingivalis (R) S. mutans (F)
PF-S003 S. epidermidis (R) ALALLKQDLLNFEGRGRIITSTYLQFNE 1566 M.
luteus (R) GCVP B. subtilis (A) P. aeruginosa (A) C. albicans (A)
MRSA (M) S. pneumoniae (D) C. jeikeium (D) C. jejuni (D) Key to
Abbreviations: (A) Peptide aggregates; (B) Less hyphal formation;
(C) Clumps; (D) Diffuse clumps and small polyps; (F) Diffuse
growth; (H) Thin; (I) Growth inhibition; (M) Microcolony formation;
(R) Rippled; (S) Small polyps; (T) Thick; (W) Halo formation on
top, microlonies on bottom. These data thus indicate
peptide-mediated interruption of bacterial biofilm formation
processes, cellular metabolism, cellular import/export, nutrient
acquisition, quorum sensing and communication, motility,
chemotaxis, replication, translation, and/or transcription.
Accordingly, without being bound to a particular theory, it is
believed that the alteration of one or more of these basic pathways
is important to pathogenesis, or the stopping thereof.
[0119] In certain embodiments, the amino acid sequence of the
antimicrobial peptides comprises or consists of a single amino acid
sequence, e.g., as listed above in Tables 4 and/or 5, and/or Table
15, and/or below in Table 14. In certain embodiments the amino acid
sequence of the antimicrobial peptides comprises two copies, three
copies, four copies, five copies six copies or more of one or more
of the amino acid sequences listed in Tables 4, and/or 5, and/or
Table 15, and/or Table 14. Thus, compound antimicrobial constructs
are contemplated where the construct comprises multiple domains
each having antimicrobial activity. The AMP domains comprising such
a construct can be the same or different. In certain embodiments
the construct comprises at least 2, at least 3, at least 4, at
least 5, at least 6, at least 7, or at least 8 different AMP
domains each domain comprising a different AMP sequence.
[0120] Various AMP domains comprising such a construct can be
joined directly to each other or two or more of such domains can be
attached to each other via a linker. An illustrative, but
non-limiting, list of suitable linkers is provided in Table 16.
Thus, in certain embodiments, two or more AMP domains comprising a
compound AMP construct are chemically conjugated together.
[0121] In certain embodiments the two or more AMP domains
comprising the AMP construct are joined by a peptide linker. Where
all the AMP domains are attached directly to each other or are
joined by peptide linkers, the entire construct can be provided as
a single-chain peptide (fusion protein).
[0122] In various embodiments, the antimicrobial peptides described
herein comprise one or more of the amino acid sequences shown in
Tables 4, and/or 5, and/or 15 and/or 14 (and/or the retro, inverso,
retroinverso, etc. forms of such sequences). In certain embodiments
the peptides range in length up to about 100 amino acids in length,
preferably up to about 80, about 70, about 60, or about 51 amino
acids in length. In certain embodiments the peptides range in
length from about 8 amino acids up to about 100 amino acids 80
amino acids, 60 amino acids or about 51 amino acids in length. In
certain embodiments the peptides range in length from about 8 up to
about 50, 40, 30, 20, 15, 15, 13, or 12 amino acids in length.
[0123] As shown in Tables 4, and/or 5, and/or 15 and/or 14, the
various amino acid sequences described herein are effective against
particular microorganisms. The range of activity of the peptides or
compositions comprising such peptides can be increased by including
amino acid sequences effective against different microorganisms
either as separate components and/or as multiple domains within a
single construct.
TABLE-US-00006 TABLE 6 Illustrative target microorganisms and
peptides effective against that target. Gram Positive Bacteria: A.
naeslundii PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525,
PF-529, PF- 148 B. subtilis PF-002, PF-005, PF-006, PF-040, PF-053,
PF-056, PF-061, PF-063, PF- 067, PF-068, PF-069, PF-070, PF-071,
PF-145, PF-148, PF-171, PF-175, PF-283, PF-289, PF-292, PF-296,
PF-297, PF-301, PF-303, PF-305, PF- 306, PF-307, PF-318, PF-319,
PF-322, PF-335, PF-339, PF-342, PF-497, PF-499, PF-527, PF-531,
PF-545, PF-547, PF-548, PF-549, PF-550, PF- 552, PF-553, PF-554,
PF-556, PF-557, PF-558, PF-559, PF-560, PF-561, PF-563, PF-564,
PF-565, PF-566, PF-569, PF-571, PF-572, PF-574, PF- 632, PF-636,
PF-655, PF-659, PF-668, PF-670, PF-672, PF-686, PF-998, PF-2003 C.
difficile PF-522, PF-531, PF-538 C. jeikeium PF-001, PF-003,
PF-004, PF-101, PF-011, PF-012, PF-013, PF-021, PF- 022, PF-025,
PF-028, PF-030, PF-032, PF-033, PF-036, PF-037, PF-040, PF-042,
PF-043, PF-046, PF-048, PF-052, PF-053, PF-056, PF-057, PF- 063,
PF-065, PF-067, PF-068, PF-073, PF-075, PF-076, PF-099, PF-124,
PF-127, PF-129, PF-133, PF-135, PF-137, PF-139, PF-140, PF-145, PF-
148, PF-164, PF-173, PF-176, PF-186, PF-188, PF-190, PF-191,
PF-196, PF-199, PF-203, PF-204, PF-208, PF-527, PF-531, PF-545,
PF-546, PF- 548, PF-553, PF-556, PF-564, PF-566, PF-567, PF-575,
PF-622, PF-523, PF-629, PF-632, PF-635, PF-637, PF-657, PF-668,
PF-672, PF-681, PF- 685, PF-S003 E. faecalis PF-007, PF-053,
PF-057, PF-068, PF-347, PF-349, PF-355, PF-356, PF- 363, PF-366,
PF-369, PF-374, PF-375, PF-376, PF-379, PF-380, PF-381, PF-386,
PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-396, PF- 398,
PF-399, PF-401, PF-407, PF-410, PF-411, PF-418, PF-422, PF-425,
PF-426, PF-427, PF-429, PF-431, PF-432, PF-439, PF-440, PF-444, PF-
447, PF-450, PF-451, PF-452, PF-454, PF-456, PF-460, PF-461,
PF-469, PF-470, PF-471, PF-472, PF-473, PF-474, PF-475, PF-480,
PF-484, PF- 514, PF-518, PF-519, PF-524, PF-530, PF-532, PF-533,
PF-534, PF-536, PF-544, PF-545, PF-546, PF-547, PF-556, PF-577,
PF-581, PF-582, PF- 584, PF-585, PF-586, PF-588, PF-591, PF-592,
PF-593, PF-594, PF-595, PF-596, PF-597, PF-598, PF-599, PF-601,
PF-602, PF-604, PF-605, PF- 607, PF-609, PF-610, PF-613, PF-614,
PF-615, PF-616, PF-617, PF-618, PF-621, PF-622, PF-623, PF-627,
PF-629, PF-631, PF-632, PF-635, PF- 636, PF-637, PF-638, PF-639,
PF-640, PF-643, PF-649, PF-657, PF-664, PF-667, PF-668, PF-672,
PF-675, PF-677, PF-681, PF-684, PF-685, PF- 686, PF-690, PF-695,
PF-698 M. luteus PF-001, PF-003, PF-004, PF-006, PF-007, PF-010,
PF-012, PF-013, PF- 020, PF-021, PF-022, PF-025, PF-030, PF-036,
PF-037, PF-040, PF-042, PF-043, PF-051, PF-052, PF-053, PF-056,
PF-057, PF-063, PF-067, PF- 068, PF-071, PF-073, PF-075, PF-076,
PF-125, PF-127, PF-137, PF-139, PF-140, PF-145, PF-148, PF-171,
PF-175, PF-176, PF-199, PF-204, PF- 212, PF-215, PF-224, PF-226,
PF-234, PF-235, PF-249, PF-250, PF-255, PF-257, PF-264, PF-270,
PF-271, PF-274, PF-276, PF-278, PF-357, PF- 527, PF-543, PF-548,
PF-556, PF-562, PF-566, PF-567, PF-578, PF-580, PF-600, PF-603,
PF-612, PF-624, PF-634, PF-741, PF-745, PF-746, PF- 761, PF-763,
PF-770, PF-776, PF-S003 MRSA PF-001, PF-003, PF-004, PF-006,
PF-007, PF-010, PF-011, PF-012, PF- 013, PF-015, PF-017, PF-019,
PF-020, PF-021, PF-022, PF-023, PF-024, PF-025, PF-026, PF-027,
PF-028, PF-029, PF-030, PF-031, PF-033, PF- 035, PF-036, PF-037,
PF-040, PF-041, PF-042, PF-043, PF-045, PF-046, PF-048, PF-049,
PF-051, PF-052, PF-053, PF-056, PF-057, PF-058, PF- 063, PF-064,
PF-065, PF-066, PF-067, PF-068, PF-071, PF-073, PF-074, PF-075,
PF-076, PF-140, PF-145, PF-148, PF-149, PF-156, PF-168, PF- 171,
PF-178, PF-191, PF-209, PF-347, PF-349, PF-350, PF-354, PF-355,
PF-356, PF-357, PF-360, PF-362, PF-366, PF-369, PF-370, PF-373, PF-
374, PF-375, PF-376, PF-378, PF-379, PF-380, PF-381, PF-382,
PF-386, PF-387, PF-389, PF-390, PF-392, PF-393, PF-394, PF-395,
PF-396, PF- 398, PF-399, PF-401, PF-403, PF-404, PF-405, PF-406,
PF-407, PF-408, PF-410, PF-411, PF-413, PF-417, PF-418, PF-422,
PF-425, PF-426, PF- 427, PF-429, PF-430, PF-431, PF-432, PF-439,
PF-440, PF-442, PF-443, PF-444, PF-447, PF-450, PF-451, PF-452,
PF-453, PF-454, PF-458, PF- 460, PF-461, PF-469, PF-471, PF-472,
PF-473, PF-474, PF-475, PF-478, PF-480, PF-518, PF-519, PF-524,
PF-526, PF-527, PF-528, PF-530, PF- 532, PF-533, PF-534, PF-536,
PF-539, PF-540, PF-543, PF-544, PF-545, PF-546, PF-547, PF-548,
PF-549, PF-551, PF-553, PF-555, PF-556, PF- 558, PF-560, PF-561,
PF-562, PF-564, PF-565, PF-566, PF-567, PF-576, PF-577, PF-578,
PF-580, PF-581, PF-583, PF-584, PF-585, PF-586, PF- 589, PF-592,
PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606,
PF-607, PF-609, PF-610, PF-612, PF-613, PF-615, PF-619, PF- 622,
PF-623, PF-624, PF-627, PF-629, PF-630, PF-632, PF-634, PF-635,
PF-637, PF-638, PF-639, PF-652, PF-643, PF-654, PF-655, PF-656, PF-
657, PF-658, PF-659, PF-661, PF-664, PF-667, PF-778, PF-672,
PF-677, PF-680, PF-683, PF-685, PF-686, PF-690, PF-692, PF-694,
PF-695, PF- 738, PF-741, PF-745, PF-746, PF-760, PF-761, PF-763,
PF-764, PF-770, PF-776, PF-S003 S. epidermidis PF-001, PF-003,
PF-004, PF-006, PF-007, PF-009, PF-010, PF-012, PF- 013, PF-020,
PF-021, PF-022, PF-024, PF-025, PF-027, PF-028, PF-030, PF-032,
PF-033, PF-034, PF-036, PF-037, PF-040, PF-041, PF-042, PF- 043,
PF-046, PF-048, PF-051, PF-052, PF-953, PF-956, PF-957, PF-961,
PF-963, PF-964, PF-965, PF-967, PF-968, PF-971, PF-073, PF-074, PF-
075, PF-076, PF-099, PF-123, PF-124, PF-125, PF-127, PF-128,
PF-129, PF-137, PF-139, PF-140, PF-145, PF-148, PF-153, PF-157,
PF-171, PF- 173, PF-176, PF-178, PF-180, PF-186, PF-190, PF-191,
PF-192, PF-196, PF-199, PF-203, PF-204, PF-208, PF-209, PF-226,
PF-233, PF-273, PF- 278, PF-283, PF-290, PF-292, PF-293, PF-294,
PF-296, PF-297, PF-301, PF-307, PF-310, PF-313, PF-318, PF-319,
PF-322, PF-335, PF-339, PF- 342, PF-347, PF-349, PF-350, PF-355,
PF-356, PF-357, PF-360, PF-363, PF-366, PF-369, PF-370, PF-373,
PF-374, PF-375, PF-376, PF-378, PF- 379, PF-380, PF-381, PF-383,
PF-386, PF-387, PF-389, PF-390, PF-393, PF-395, PF-396, PF-397,
PF-398, PF-399, PF-401, PF-403, PF-404, PF- 406, PF-407, PF-408,
PF-410, PF-411, PF-413, PF-417, PF-418, PF-422, PF-425, PF-246,
PF-249, PF-430, PF-431, PF-432, PF-439, PF-440, PF- 444, PF-447,
PF-451, PF-452, PF-453, PF-454, PF-460, PF-469, PF-471, PF-473,
PF-474, PF-475, PF-478, PF-480, PF-514, PF-518, PF-526, PF- 527,
PF-528, PF-530, PF-531, PF-533, PF-534, PF-536, PF-540, PF-543,
PF-544, PF-546, PF-547, PF-548, PF-556, PF-558, PF-562, PF-576, PF-
577, PF-578, PF-580, PF-583, PF-584, PF-585, PF-586, PF-592,
PF-595, PF-596, PF-598, PF-599, PF-600, PF-603, PF-605, PF-606,
PF-607, PF- 610, PF-612, PF-613, PF-614, PF-615, PF-616, PF-619,
PF-622, PF-623, PF-624, PF-627, PF-632, PF-634, PF-635, PF-637,
PF-638, PF-655, PF- 657, PF-659, PF-664, PF-667, PF-778, PF-672,
PF-677, PF-681, PF-683, PF-685, PF-686, PF-690, PF-741, PF-746,
PF-760, PF-761, PF-763, PF- 770, PF-776, PF-S003 S. mutans G-1,
G-2, G-4, G-8, PF-020, PF-040, PF-051, PF-531, PF-543, PF-547,
PF-578, PF-583, PF-600, PF-606, PF-612, PF-624, PF-634, PF-741, PF-
745, PF-746, PF-761, PF-770, PF-776, PF-C055, PF-C057, PF-C058, PF-
C061, PF-C062, PF-C072, PF-C075, PF-C084, PF-C085, PF-C088, PF-
C098, PF-C131, PF-C135, PF-C139, PF-C142, PF-C146, PF-C180, PF-
C194, PF-C281, PF-C290, PF-C291, PF-C293 S. pneumoniae PF-002,
PF-005, PF-006, PF-020, PF-033, PF-040, PF-051, PF-053, PF- 056,
PF-057, PF-061, PF-063, PF-068, PF-071, PF-073, PF-140, PF-144,
PF-145, PF-148, PF-171, PF-175, PF-178, PF-220, PF-355, PF-356, PF-
357, PF-363, PF-366, PF-380, PF-389, PF-390, PF-393, PF-407,
PF-411, PF-414, PF-415, PF-416, PF-417, PF-418, PF-419, PF-421,
PF-422, PF- 423, PF-424, PF-425, PF-426, PF-427, PF-428, PF-429,
PF-430, PF-431, PF-432, PF-433, PF-434, PF-437, PF-439, PF-440,
PF-442, PF-443, PF- 444, PF-445, PF-446, PF-447, PF-448, PF-449,
PF-450, PF-451, PF-452, PF-453, PF-454, PF-455, PF-457, PF-458,
PF-469, PF-460, PF-461, PF- 462, PF-464, PF-465, PF-466, PF-467,
PF-468, PF-469, PF-471, PF-472, PF-473, PF-474, PF-475, PF-476,
PF-477, PF-478, PF-479, PF-480, PF- 482, PF-485, PF-511, PF-512,
PF-513, PF-514, PF-515, PF-516, PF-517, PF-518, PF-519, PF-520,
PF-521, PF-522, PF-523, PF-524, PF-525, PF- 526, PF-527, PF-528,
PF-529, PF-530, PF-531, PF-532, PF-533, PF-534, PF-535, PF-536,
PF-537, PF-538, PF-539, PF-540, PF-541, PF-542, PF- 543, PF-544,
PF-546, PF-548, PF-553, PF-555, PF-556, PF-558, PF-560, PF-562,
PF-563, PF-566, PF-567, PF-572, PF-573, PF-575, PF-576, PF- 577,
PF-578, PF-580, PF-581, PF-583, PF-585, PF-585, PF-586, PF-587,
PF-589, PF-591, PF-592, PF-595, PF-596, PF-598, PF-599, PF-600, PF-
603, PF-605, PF-606, PF-607, PF-609, PF-610, PF-612, PF-614,
PF-615, PF-617, PF-618, PF-619, PF-621, PF-622, PF-623, PF-624,
PF-625, PF- 626, PF-627, PF-629, PF-631, PF-632, PF-634, PF-635,
PF-636, PF-637, PF-638, PF-639, PF-640, PF-643, PF-644, PF-645,
PF-646, PF-647, PF- 651, PF-652, PF-653, PF-654, PF-655, PF-657,
PF-658, PF-659, PF-660, PF-662, PF-663, PF-664, PF-665, PF-666,
PF-667, PF-668, PF-670, PF- 672, PF-675, PF-677, PF-681, PF-682,
PF-683, PF-684, PF-685, PF-686, PF-687, PF-688, PF-690, PF-691,
PF-693, PF-694, PF-695, PF-696, PF- 697, PF-698, PF-699, PF-700,
PF-702, PF-704, PF-737, PF-741, PF-744, PF-745, PF-746, PF-748,
PF-749, PF-752, PF-756, PF-757, PF-760, PF- 761, PF-762, PF-763,
PF-764, PF-770, PF-776, PF-S003 Gram Negative Bacteria: A.
baumannii PF-531, PF-006, PF-538, PF-530 C. jejuni PF-006, PF-008,
PF-033, PF-040, PF-053, PF-056, PF-057, PF-059, PF- 061, PF-063,
PF-067, PF-068, PF-069, PF-071, PF-073, PF-140, PF-145, PF-148,
PF-171, PF-175, PF-355, PF-356, PF-363, PF-366, PF-380, PF- 389,
PF-390, PF-392, PF-393, PF-411, PF-418, PF-422, PF-425, PF-426,
PF-431, PF-432, PF-456, PF-469, PF-470, PF-471, PF-472, PF-473, PF-
474, PF-475, PF-527, PF-548, PF-555, PF-556, PF-558, PF-559,
PF-560, PF-562, PF-563, PF-564, PF-566, PF-567, PF-575, PF-576,
PF-577, PF- 581, PF-584, PF-585, PF-586, PF-590, PF-591, PF-592,
PF-595, PF-596, PF-598, PF-599, PF-601, PF-605, PF-607, PF-609,
PF-610, PF-614, PF- 615, PF-S003 E. coli PF-007, PF-040, PF-053,
PF-057, PF-068, PF-178, PF-344, PF-347, PF- 349, PF-350, PF-355,
PF-360, PF-362, PF-363, PF-366, PF-369, PF-370, PF-374, PF-375,
PF-376, PF-379, PF-380, PF-381, PF-383, PF-385, PF- 386, PF-387,
PF-390, PF-395, PF-396, PF-398, PF-399, PF-401, PF-403, PF-410,
PF-411, PF-413, PF-418, PF-425, PF-426, PF-427, PF-432, PF- 439,
PF-440, PF-443, PF-444, PF-451, PF-452, PF-453, PF-454, PF-460,
PF-469, PF-471, PF-473, PF-474, PF-478, PF-480, PF-514, PF-518, PF-
519, PF-524, PF-526, PF-528, PF-530, PF-531, PF-532, PF-533,
PF-534, PF-536, PF-540, PF-541, PF-543, PF-546, PF-576, PF-577,
PF-578, PF- 584, PF-586, PF-592, PF-595, PF-596, PF-598, PF-600,
PF-603, PF-605, PF-606, PF-610, PF-612, PF-615, PF-619, PF-624,
PF-634, PF-741, PF- 746, PF-761, PF-770, PF-776 F. nucleatum
PF-C055, PF-C061, PF-C062, PF-C064, PF-C065, PF-C069, PF-C071,
PF-C072, PF-C075, PF-C084, PF-C086, PF-C088, PF-C091, PF-C095,
PF-C098, PF-C120, PF-C131, PF-C135, PF-C136, PF-C137, PF-C143,
PF-C145, PF-C181, PF-C194, PF-C214, PF-C291, PF-C293 M. xanthus
G-5, G-6, G-7 P. aeruginosa PF-053, PF-063, PF-067, PF-128, PF-140,
PF-143, PF-168, PF-204, PF- 209, PF-355, PF-356, PF-366, PF-380,
PF-411, PF-425, PF-432, PF-454, PF-458, PF-471, PF-474, PF-527,
PF-531, PF-535, PF-536, PF-575, PF- 577, PF-605, PF-746, PF-761,
PF-S003 P. gingivalis PF-C052, PF-C072, PF-C075, PF-C084, PF-C088,
PF-C089, PF-C136, PF-C180, PF-C194, C293 P. mirabilis PF-040,
PF-578, PF-612, PF-624, PF-634, PF-741, PF-770 Yeast Fungi: A.
niger PF-531, PF-527, PF-672, PF-545, PF-168, PF-448, PF-525,
PF-529, PF- 148 C. albicans PF-053, PF-056, PF-057, PF-071, PF-140,
PF-148, PF-175, PF-278, PF- 307, PF-425, PF-426, PF-474, PF-475,
PF-526, PF-527, PF-528, PF-545, PF-605, PF-606, PF-617, PF-627,
PF-632, PF-635, PF-636, PF-639, PF- 640, PF-645, PF-646, PF-647,
PF-654, PF-668, PF-672, PF-684, PF-686, PF-697, PF-698, PF-S003 T.
rubrum PF-283, PF-307, PF-527, PF-531, PF-547, PF-672
[0124] In certain embodiments the activity against a particular
microorganism or group of microorganisms can be increased by
increasing the number of peptides or peptide domains with activity
against that microorganism or group of microorganisms.
[0125] Thus, for example, in certain embodiments, a peptide or
composition effective to kill or inhibit the growth and/or
proliferation of a yeast or fungus can comprise or more peptides
and/or one or more peptide domains having sequences selected from
the sequences shown in Tables 4, 5, or 6 (e.g., PF-S003, PF-053,
PF-056, PF-057, PF-071, PF-140, PF-148, PF-168, PF-175, PF-278,
PF-283, PF-307, PF-425, PF-426, PF-448, PF-474, PF-475, PF-525,
PF-526, PF-527, PF-528, PF-529, PF-531, PF-545, PF-547, PF-606,
PF-617, PF-627, PF-632, PF-635, PF-636, PF-639, PF-640, PF-645,
PF-646, PF-647, PF-654, PF-668, PF-672, PF-684, PF-686, PF-697, and
PF-69)8. A peptide or composition effective to kill or inhibit the
growth and/or proliferation of Aspergillus niger can comprise one
or more peptides and/or one or more peptide domains having
sequences selected from the group consisting of PF-531, PF-527,
PF-672, PF-545, PF-168, PF-448, PF-525, PF-529, and PF-148. A
peptide or composition effective to kill or inhibit the growth
and/or proliferation of Candida albicans can comprise one or more
peptides and/or one or more peptide domains having sequences
selected from the group consisting of PF-053, PF-056, PF-057,
PF-071, PF-140, PF-148, PF-175, PF-278, PF-307, PF-425, PF-426,
PF-474, PF-475, PF-526, PF-527, PF-528, PF-545, PF-605, PF-606,
PF-617, PF-627, PF-632, PF-635, PF-636, PF-639, PF-640, PF-645,
PF-646, PF-647, PF-654, PF-668, PF-672, PF-684, PF-686, PF-697,
PF-698, and PF-S003. A peptide or composition effective to kill or
inhibit the growth and/or proliferation of Trichophyton rubrum can
comprise one or more peptides and/or one or more peptide domains
having sequences selected from the group consisting of PF-283,
PF-307, PF-527, PF-531, PF-547, and PF-672.
[0126] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of a bacterium can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against a bacterium in Tables 4, 5, or 6.
[0127] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of a gram positive
bacterium can comprise one or more peptides and/or one or more
peptide domains comprising or consisting of sequences identified as
having activity against a gram positive bacterium in Tables 4, 5,
or 6. In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of a gram negative
bacterium can comprise one or more peptides and/or one or more
peptide domains comprising or consisting of sequences identified as
having activity against a gram negative bacterium in Tables 4, 5,
or 6.
[0128] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of A. naeslundii
can comprise one or more peptides and/or one or more peptide
domains comprising or consisting of sequences identified as having
activity against A. Naeslundii in Tables 4, 5, or 6 (e.g., from the
group consisting of PF-531, PF-527, PF-672, PF-545, PF-168, PF-448,
PF-525, PF-529, and PF-148).
[0129] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of B. subtilis can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against B. subtilis in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-002, PF-005, PF-006, PF-040, PF-053, PF-056,
PF-061, PF-063, PF-067, PF-068, PF-069, PF-070, PF-071, PF-145,
PF-148, PF-171, PF-175, PF-283, PF-289, PF-292, PF-296, PF-297,
PF-301, PF-303, PF-305, PF-306, PF-307, PF-318, PF-319, PF-322,
PF-335, PF-339, PF-342, PF-497, PF-499, PF-527, PF-531, PF-545,
PF-547, PF-548, PF-549, PF-550, PF-552, PF-553, PF-554, PF-556,
PF-557, PF-558, PF-559, PF-560, PF-561, PF-563, PF-564, PF-565,
PF-566, PF-569, PF-571, PF-572, PF-574, PF-632, PF-636, PF-655,
PF-659, PF-668, PF-670, PF-672, PF-686, PF-998, and PF-2003).
[0130] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of C. difficile can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against C. difficile in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-522, PF-531, and PF-538).
[0131] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of C. jeikeium can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against C. jeikeium in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-001, PF-003, PF-004, PF-101, PF-011, PF-012,
PF-013, PF-021, PF-022, PF-025, PF-028, PF-030, PF-032, PF-033,
PF-036, PF-037, PF-040, PF-042, PF-043, PF-046, PF-048, PF-052,
PF-053, PF-056, PF-057, PF-063, PF-065, PF-067, PF-068, PF-073,
PF-075, PF-076, PF-099, PF-124, PF-127, PF-129, PF-133, PF-135,
PF-137, PF-139, PF-140, PF-145, PF-148, PF-164, PF-173, PF-176,
PF-186, PF-188, PF-190, PF-191, PF-196, PF-199, PF-203, PF-204,
PF-208, PF-527, PF-531, PF-545, PF-546, PF-548, PF-553, PF-556,
PF-564, PF-566, PF-567, PF-575, PF-622, PF-523, PF-629, PF-632,
PF-635, PF-637, PF-657, PF-668, PF-672, PF-681, PF-685, and
PF-S003).
[0132] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of E. faecalis can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against E. faecalis in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-007, PF-053, PF-057, PF-068, PF-347, PF-349,
PF-355, PF-356, PF-363, PF-366, PF-369, PF-374, PF-375, PF-376,
PF-379, PF-380, PF-381, PF-386, PF-387, PF-389, PF-390, PF-392,
PF-393, PF-394, PF-396, PF-398, PF-399, PF-401, PF-407, PF-410,
PF-411, PF-418, PF-422, PF-425, PF-426, PF-427, PF-429, PF-431,
PF-432, PF-439, PF-440, PF-444, PF-447, PF-450, PF-451, PF-452,
PF-454, PF-456, PF-460, PF-461, PF-469, PF-470, PF-471, PF-472,
PF-473, PF-474, PF-475, PF-480, PF-484, PF-514, PF-518, PF-519,
PF-524, PF-530, PF-532, PF-533, PF-534, PF-536, PF-544, PF-545,
PF-546, PF-547, PF-556, PF-577, PF-581, PF-582, PF-584, PF-585,
PF-586, PF-588, PF-591, PF-592, PF-593, PF-594, PF-595, PF-596,
PF-597, PF-598, PF-599, PF-601, PF-602, PF-604, PF-605, PF-607,
PF-609, PF-610, PF-613, PF-614, PF-615, PF-616, PF-617, PF-618,
PF-621, PF-622, PF-623, PF-627, PF-629, PF-631, PF-632, PF-635,
PF-636, PF-637, PF-638, PF-639, PF-640, PF-643, PF-649, PF-657,
PF-664, PF-667, PF-668, PF-672, PF-675, PF-677, PF-681, PF-684,
PF-685, PF-686, PF-690, PF-695, and PF-698).
[0133] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of M. luteus can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against M. luteus in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-001, PF-003, PF-004, PF-006, PF-007, PF-010,
PF-012, PF-013, PF-020, PF-021, PF-022, PF-025, PF-030, PF-036,
PF-037, PF-040, PF-042, PF-043, PF-051, PF-052, PF-053, PF-056,
PF-057, PF-063, PF-067, PF-068, PF-071, PF-073, PF-075, PF-076,
PF-125, PF-127, PF-137, PF-139, PF-140, PF-145, PF-148, PF-171,
PF-175, PF-176, PF-199, PF-204, PF-212, PF-215, PF-224, PF-226,
PF-234, PF-235, PF-249, PF-250, PF-255, PF-257, PF-264, PF-270,
PF-271, PF-274, PF-276, PF-278, PF-357, PF-527, PF-543, PF-548,
PF-556, PF-562, PF-566, PF-567, PF-578, PF-580, PF-600, PF-603,
PF-612, PF-624, PF-634, PF-741, PF-745, PF-746, PF-761, PF-763,
PF-770, PF-776, and PF-S003).
[0134] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of MRSA can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against MRSA in Tables 4, 5, or 6 (e.g., from the group consisting
of PF-001, PF-003, PF-004, PF-006, PF-007, PF-010, PF-011, PF-012,
PF-013, PF-015, PF-017, PF-019, PF-020, PF-021, PF-022, PF-023,
PF-024, PF-025, PF-026, PF-027, PF-028, PF-029, PF-030, PF-031,
PF-033, PF-035, PF-036, PF-037, PF-040, PF-041, PF-042, PF-043,
PF-045, PF-046, PF-048, PF-049, PF-051, PF-052, PF-053, PF-056,
PF-057, PF-058, PF-063, PF-064, PF-065, PF-066, PF-067, PF-068,
PF-071, PF-073, PF-074, PF-075, PF-076, PF-140, PF-145, PF-148,
PF-149, PF-156, PF-168, PF-171, PF-178, PF-191, PF-209, PF-347,
PF-349, PF-350, PF-354, PF-355, PF-356, PF-357, PF-360, PF-362,
PF-366, PF-369, PF-370, PF-373, PF-374, PF-375, PF-376, PF-378,
PF-379, PF-380, PF-381, PF-382, PF-386, PF-387, PF-389, PF-390,
PF-392, PF-393, PF-394, PF-395, PF-396, PF-398, PF-399, PF-401,
PF-403, PF-404, PF-405, PF-406, PF-407, PF-408, PF-410, PF-411,
PF-413, PF-417, PF-418, PF-422, PF-425, PF-426, PF-427, PF-429,
PF-430, PF-431, PF-432, PF-439, PF-440, PF-442, PF-443, PF-444,
PF-447, PF-450, PF-451, PF-452, PF-453, PF-454, PF-458, PF-460,
PF-461, PF-469, PF-471, PF-472, PF-473, PF-474, PF-475, PF-478,
PF-480, PF-518, PF-519, PF-524, PF-526, PF-527, PF-528, PF-530,
PF-532, PF-533, PF-534, PF-536, PF-539, PF-540, PF-543, PF-544,
PF-545, PF-546, PF-547, PF-548, PF-549, PF-551, PF-553, PF-555,
PF-556, PF-558, PF-560, PF-561, PF-562, PF-564, PF-565, PF-566,
PF-567, PF-576, PF-577, PF-578, PF-580, PF-581, PF-583, PF-584,
PF-585, PF-586, PF-589, PF-592, PF-595, PF-596, PF-598, PF-599,
PF-600, PF-603, PF-605, PF-606, PF-607, PF-609, PF-610, PF-612,
PF-613, PF-615, PF-619, PF-622, PF-623, PF-624, PF-627, PF-629,
PF-630, PF-632, PF-634, PF-635, PF-637, PF-638, PF-639, PF-652,
PF-643, PF-654, PF-655, PF-656, PF-657, PF-658, PF-659, PF-661,
PF-664, PF-667, PF-778, PF-672, PF-677, PF-680, PF-683, PF-685,
PF-686, PF-690, PF-692, PF-694, PF-695, PF-738, PF-741, PF-745,
PF-746, PF-760, PF-761, PF-763, PF-764, PF-770, PF-776, and
PF-S003).
[0135] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of S. epidermidis
can comprise one or more peptides and/or one or more peptide
domains comprising or consisting of sequences identified as having
activity against of S. epidermidis in Tables 4, 5, or 6 (e.g., from
the group consisting of PF-001, PF-003, PF-004, PF-006, PF-007,
PF-009, PF-010, PF-012, PF-013, PF-020, PF-021, PF-022, PF-024,
PF-025, PF-027, PF-028, PF-030, PF-032, PF-033, PF-034, PF-036,
PF-037, PF-040, PF-041, PF-042, PF-043, PF-046, PF-048, PF-051,
PF-052, PF-953, PF-956, PF-957, PF-961, PF-963, PF-964, PF-965,
PF-967, PF-968, PF-971, PF-073, PF-074, PF-075, PF-076, PF-099,
PF-123, PF-124, PF-125, PF-127, PF-128, PF-129, PF-137, PF-139,
PF-140, PF-145, PF-148, PF-153, PF-157, PF-171, PF-173, PF-176,
PF-178, PF-180, PF-186, PF-190, PF-191, PF-192, PF-196, PF-199,
PF-203, PF-204, PF-208, PF-209, PF-226, PF-233, PF-273, PF-278,
PF-283, PF-290, PF-292, PF-293, PF-294, PF-296, PF-297, PF-301,
PF-307, PF-310, PF-313, PF-318, PF-319, PF-322, PF-335, PF-339,
PF-342, PF-347, PF-349, PF-350, PF-355, PF-356, PF-357, PF-360,
PF-363, PF-366, PF-369, PF-370, PF-373, PF-374, PF-375, PF-376,
PF-378, PF-379, PF-380, PF-381, PF-383, PF-386, PF-387, PF-389,
PF-390, PF-393, PF-395, PF-396, PF-397, PF-398, PF-399, PF-401,
PF-403, PF-404, PF-406, PF-407, PF-408, PF-410, PF-411, PF-413,
PF-417, PF-418, PF-422, PF-425, PF-246, PF-249, PF-430, PF-431,
PF-432, PF-439, PF-440, PF-444, PF-447, PF-451, PF-452, PF-453,
PF-454, PF-460, PF-469, PF-471, PF-473, PF-474, PF-475, PF-478,
PF-480, PF-514, PF-518, PF-526, PF-527, PF-528, PF-530, PF-531,
PF-533, PF-534, PF-536, PF-540, PF-543, PF-544, PF-546, PF-547,
PF-548, PF-556, PF-558, PF-562, PF-576, PF-577, PF-578, PF-580,
PF-583, PF-584, PF-585, PF-586, PF-592, PF-595, PF-596, PF-598,
PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-610, PF-612,
PF-613, PF-614, PF-615, PF-616, PF-619, PF-622, PF-623, PF-624,
PF-627, PF-632, PF-634, PF-635, PF-637, PF-638, PF-655, PF-657,
PF-659, PF-664, PF-667, PF-778, PF-672, PF-677, PF-681, PF-683,
PF-685, PF-686, PF-690, PF-741, PF-746, PF-760, PF-761, PF-763,
PF-770, PF-776, and PF-S003).
[0136] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of S. mutans can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against S. mutans in Tables 4, 5, or 6 (e.g., from the group
consisting of G-1, G-2, G-4, G-8, PF-020, PF-040, PF-051, PF-531,
PF-543, PF-547, PF-578, PF-583, PF-600, PF-606, PF-612, PF-624,
PF-634, PF-741, PF-745, PF-746, PF-761, PF-770, PF-776, PF-C055,
PF-C057, PF-C058, PF-C061, PF-C062, PF-C072, PF-C075, PF-C084,
PF-C085, PF-C088, PF-C098, PF-C131, PF-C135, PF-C139, PF-C142,
PF-C146, PF-C180, PF-C194, PF-C281, PF-C290, PF-C291, PF-C293
[0137] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of S. pneumoniae
can comprise one or more peptides and/or one or more peptide
domains comprising or consisting of sequences identified as having
activity against S. pneumoniae in Tables 4, 5, or 6 (e.g., from the
group consisting of PF-002, PF-005, PF-006, PF-020, PF-033, PF-040,
PF-051, PF-053, PF-056, PF-057, PF-061, PF-063, PF-068, PF-071,
PF-073, PF-140, PF-144, PF-145, PF-148, PF-171, PF-175, PF-178,
PF-220, PF-355, PF-356, PF-357, PF-363, PF-366, PF-380, PF-389,
PF-390, PF-393, PF-407, PF-411, PF-414, PF-415, PF-416, PF-417,
PF-418, PF-419, PF-421, PF-422, PF-423, PF-424, PF-425, PF-426,
PF-427, PF-428, PF-429, PF-430, PF-431, PF-432, PF-433, PF-434,
PF-437, PF-439, PF-440, PF-442, PF-443, PF-444, PF-445, PF-446,
PF-447, PF-448, PF-449, PF-450, PF-451, PF-452, PF-453, PF-454,
PF-455, PF-457, PF-458, PF-469, PF-460, PF-461, PF-462, PF-464,
PF-465, PF-466, PF-467, PF-468, PF-469, PF-471, PF-472, PF-473,
PF-474, PF-475, PF-476, PF-477, PF-478, PF-479, PF-480, PF-482,
PF-485, PF-511, PF-512, PF-513, PF-514, PF-515, PF-516, PF-517,
PF-518, PF-519, PF-520, PF-521, PF-522, PF-523, PF-524, PF-525,
PF-526, PF-527, PF-528, PF-529, PF-530, PF-531, PF-532, PF-533,
PF-534, PF-535, PF-536, PF-537, PF-538, PF-539, PF-540, PF-541,
PF-542, PF-543, PF-544, PF-546, PF-548, PF-553, PF-555, PF-556,
PF-558, PF-560, PF-562, PF-563, PF-566, PF-567, PF-572, PF-573,
PF-575, PF-576, PF-577, PF-578, PF-580, PF-581, PF-583, PF-585,
PF-585, PF-586, PF-587, PF-589, PF-591, PF-592, PF-595, PF-596,
PF-598, PF-599, PF-600, PF-603, PF-605, PF-606, PF-607, PF-609,
PF-610, PF-612, PF-614, PF-615, PF-617, PF-618, PF-619, PF-621,
PF-622, PF-623, PF-624, PF-625, PF-626, PF-627, PF-629, PF-631,
PF-632, PF-634, PF-635, PF-636, PF-637, PF-638, PF-639, PF-640,
PF-643, PF-644, PF-645, PF-646, PF-647, PF-651, PF-652, PF-653,
PF-654, PF-655, PF-657, PF-658, PF-659, PF-660, PF-662, PF-663,
PF-664, PF-665, PF-666, PF-667, PF-668, PF-670, PF-672, PF-675,
PF-677, PF-681, PF-682, PF-683, PF-684, PF-685, PF-686, PF-687,
PF-688, PF-690, PF-691, PF-693, PF-694, PF-695, PF-696, PF-697,
PF-698, PF-699, PF-700, PF-702, PF-704, PF-737, PF-741, PF-744,
PF-745, PF-746, PF-748, PF-749, PF-752, PF-756, PF-757, PF-760,
PF-761, PF-762, PF-763, PF-764, PF-770, PF-776, and PF-S003).
[0138] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of A. baumannii can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against A. baumannii in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-531, PF-006, PF-538, and PF-530).
[0139] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of C. jejuni can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against C. jejuni in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-006, PF-008, PF-033, PF-040, PF-053, PF-056,
PF-057, PF-059, PF-061, PF-063, PF-067, PF-068, PF-069, PF-071,
PF-073, PF-140, PF-145, PF-148, PF-171, PF-175, PF-355, PF-356,
PF-363, PF-366, PF-380, PF-389, PF-390, PF-392, PF-393, PF-411,
PF-418, PF-422, PF-425, PF-426, PF-431, PF-432, PF-456, PF-469,
PF-470, PF-471, PF-472, PF-473, PF-474, PF-475, PF-527, PF-548,
PF-555, PF-556, PF-558, PF-559, PF-560, PF-562, PF-563, PF-564,
PF-566, PF-567, PF-575, PF-576, PF-577, PF-581, PF-584, PF-585,
PF-586, PF-590, PF-591, PF-592, PF-595, PF-596, PF-598, PF-599,
PF-601, PF-605, PF-607, PF-609, PF-610, PF-614, PF-615, and
PF-S003).
[0140] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of E. coli can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against E. coli in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-007, PF-040, PF-053, PF-057, PF-068, PF-178,
PF-344, PF-347, PF-349, PF-350, PF-355, PF-360, PF-362, PF-363,
PF-366, PF-369, PF-370, PF-374, PF-375, PF-376, PF-379, PF-380,
PF-381, PF-383, PF-385, PF-386, PF-387, PF-390, PF-395, PF-396,
PF-398, PF-399, PF-401, PF-403, PF-410, PF-411, PF-413, PF-418,
PF-425, PF-426, PF-427, PF-432, PF-439, PF-440, PF-443, PF-444,
PF-451, PF-452, PF-453, PF-454, PF-460, PF-469, PF-471, PF-473,
PF-474, PF-478, PF-480, PF-514, PF-518, PF-519, PF-524, PF-526,
PF-528, PF-530, PF-531, PF-532, PF-533, PF-534, PF-536, PF-540,
PF-541, PF-543, PF-546, PF-576, PF-577, PF-578, PF-584, PF-586,
PF-592, PF-595, PF-596, PF-598, PF-600, PF-603, PF-605, PF-606,
PF-610, PF-612, PF-615, PF-619, PF-624, PF-634, PF-741, PF-746,
PF-761, PF-770, and PF-776).
[0141] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of F. nucleatum can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against F. nucleatum in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-C055, PF-C061, PF-C062, PF-C064, PF-C065, PF-C069,
PF-C071, PF-C072, PF-C075, PF-C084, PF-C086, PF-C088, PF-C091,
PF-C095, PF-C098, PF-C120, PF-C131, PF-C135, PF-C136, PF-C137,
PF-C143, PF-C145, PF-C181, PF-C194, PF-C214, PF-C291, and
PF-C293).
[0142] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of M. Xanthus can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against M. Xanthus in Tables 4, 5, or 6 (e.g., from the group
consisting of G-5, G-6, and G-7).
[0143] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of P. aeruginosa
can comprise one or more peptides and/or one or more peptide
domains comprising or consisting of sequences identified as having
activity against P. aeruginosa in Tables 4, 5, or 6 (e.g., from the
group consisting of PF-053, PF-063, PF-067, PF-128, PF-140, PF-143,
PF-168, PF-204, PF-209, PF-355, PF-356, PF-366, PF-380, PF-411,
PF-425, PF-432, PF-454, PF-458, PF-471, PF-474, PF-527, PF-531,
PF-535, PF-536, PF-575, PF-577, PF-605, PF-746, PF-761, and
PF-S003).
[0144] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of P. gingivalis
can comprise one or more peptides and/or one or more peptide
domains comprising or consisting of sequences identified as having
activity against P. gingivalis in Tables 4, 5, or 6 (e.g., from the
group consisting of PF-C052, PF-C072, PF-C075, PF-C084, PF-C088,
PF-0089, PF-C136, PF-C180, PF-C194, and C293).
[0145] In certain embodiments a peptide or composition effective to
kill or inhibit the growth and/or proliferation of P. mirabilis can
comprise one or more peptides and/or one or more peptide domains
comprising or consisting of sequences identified as having activity
against P. mirabilis in Tables 4, 5, or 6 (e.g., from the group
consisting of PF-040, PF-578, PF-612, PF-624, PF-634, PF-741, and
PF-770).
[0146] It was also a surprising discovery that a number of novel
antimicrobial peptides are characterized by the presence of
particular amino acid motifs. Such motifs include KIF, FIK, KIH,
HIK, and KIV, as illustrated in Table 7.
TABLE-US-00007 TABLE 7 Antimicrobial peptides characterized by
particular motifs. SEQ ID Motif Omnibus # Sequence NO KIF PF-278
LSLATFAKIFMTRSNWSLKRFNRL 1567 PF-C059
QKIIDMSKFLFSLILFIMIVVIYIGKSIGGYSAIVSS 1568 IMLELDTVLYNKKIFFIYK
PF-C073 FESLLPQATKKIVNNKGSKINKIF 1569 PF-C085
KKFKIFVIINWFYHKYIILNFEENF 1570 PF-531 YIQFHLNQQPRPKVKKIKIFL 1571
PF-C194 NTNDLLQAFELMGLGMAGVFIVLGILYIVAELLI 1572 KIFPVNN PF-C201
IFKLFEEHLLYLLDAFYYSKIFRRLKQGLYRRKE 1573 QPYTQDLFRM PF-442
MQIFYIKTKIFLSFFLFLLIFSQCFYKIEE 1574 PF-C252 NYRLVNAIFSKIFKKKFIKF
1575 FIK PF-251 MAWKFIKLDKVVSQKECNNFLEKEENKKLLKL 1576 LRIQKNMR
PF-261 MDIWKFIKSFNTVNTYLLLSCVLLIILVLYFYVI 1577 NPA PF-497
LVLRICTDLFTFIKWTIKQRKS 1578 PF-775 DLCGQEFIKFKTCVTNQLAKK 1579
PF-591 DLLKSLLGQDGAKNDEIIEFIKIIMEK 1580 PF-597 DEIKVSDEEIEKFIKENNL
1581 PF-608 LICEVVKPEEDFIKVKLNEDNVTAKISREFIAKKI 1582 DA IT-133
YFIKDDNEALSKDWEVIGNDLKGTIDKYGKEFK 1583 VR PF-C252
NYRLVNAIFSKIFKKKFIKF 1584 PF-C278 DMKIIKLYIKILSFLFIKYCNKKLNSVKLKA
1585 PF-C290 GNVHPESDFHNLIQFIKTFLYFTIFFKYFL 1586 PF-006
MGIIAGIIKFIKGLIEKFTGK 1587 PF-013 LIQKGLNQTFIVVIRLNNFIKKS 1588
PF-040 MIHLTKQNTMEALHFIKQFYDMFFILNFNV 1589 KIH PF-252
MKKLVAALAVIVILTGCVYDPVNYDKIHDQEF 1590 QDHLRQNG PF-575
LNFRAENKILEKIHISLIDTVEGSA 1591 PF-533 KTPNDKIHKTIIIKHIIL 1592 HIK
PF-222 HIKETR 1593 PF-319 SIGSMIGMYSFRHKTKHIKFTFGIPFILFLQFLLV 1594
YFYILK PF-477 HKNKLNIPHIKS 1595 KIV PF-272
MTLTIKIKHRSKIVPLNLISLVYAFFTYNFVANRI 1596 MFLTND PF-758 PEIIKIVSGLL
1597 PF-336 MLTSRKKRLKKIVEEQNKKDESI 1598 PF-C073
FESLLPQATKKIVNNKGSKINKIF 1599 PF-721 TEQAKKIVDILNNWLE 1600 PF-730
FEDIEQIIKYHLIDGKIVAPLLLDR 1601 PF-095 KRGSKIVIAIAVVLIVLAGVWVW 1602
PF-028 ALDCSEQSVILWYETILDKIVGVIK 1603 VIK PF-257
VWENRKKYLENEIERHNVFLKLGQEVIKGLNA 1604 LASRGR PF-226
LMFFSENMDKRDTLSGKFRYFAGSKVIKLMNW 1605 LSENGK PF-580
EILNNNQVIKELTMKYKTQFESNLGGWTARARR 1606 PF-366 ALCSVIKAIELGIINVHLQ
1607 PF-C092 NGDKKAKEELDKWDEVIKELNIQF 1608 PF-S028
GSVIKKRRKRMSKKKHRKMLRRTRVQRRKLGK 1609 PF-103 VIKISVPGQVQMLIP 1610
PF-527 GSVIKKRRKRMAKKKHRKLLKKTRIQRRRAGK 1611 PF-167
AIEGVIKKGACFKLLRHEMF 1612 PF-C166 KRKHENVIVAEEMRVIKN 1613 PF-007
MGIIAGIIKVIKSLIEQFTGK 1614 PF-071 HCVIGNVVDIANLLKRRAVYRDIADVIKMR
1615 PF-028 ALDCSEQSVILWYETILDKIVGVIK 1616 PRP PF-C031
WSESQPPTATPRPHAEVARAGLVTPPTL 1617 PF-752
LHVIRPRPELSELKFPITKILKVNKQGLKK 1618 PF-672
MRFGSLALVAYDSAIKHSWPRPSSVRRLRM 1619 PF-088 VMFVLTRGRSPRPMIPAY 1620
PF-143 LSPRPIIVSRRSRADNNNDWSR 1621 PF-168
VLPFPAIPLSRRRACVAAPRPRSRQRAS 1622 PF-531 YIQFHLNQQPRPKVKKIKIFL 1623
All groups are associated with antimicrobial activity
All groups are associated with antimicrobial activity
[0147] In certain embodiments, peptides described herein can have
multiple activities. Thus for example, a peptide can have both
binding/targeting activity and antimicrobial activity. Illustrative
peptides having multiple activities are shown in Table 8. Such
peptides can be used, e.g., in a chimeric construct, for any or all
of these properties. Thus, for example, a peptide designated "B" in
Table 8 can be used as a targeting peptide. If it is also
designated G or M it can also be used for antimicrobial
activity.
Table 8. Peptides Having Multiple Activities. B: Targeting/Binding
Activity; M: Antimicrobial Activity; G: GROWTH or Phenotype
Altering.
TABLE-US-00008 TABLE 8 Peptides having multiple activities. Peptide
Activities PF-001 G B PF-002 G B PF-003 G B PF-004 G B PF-005 G B
PF-006 G B M PF-007 G B PF-008 G B PF-009 G B PF-010 G B PF-011 G B
PF-012 G B PF-013 G B PF-015 G B PF-017 G B PF-020 G B PF-021 G B
PF-022 G B PF-023 G B PF-024 G B PF-025 G B PF-026 G B PF-027 G B
PF-028 G B PF-029 G B PF-030 G B PF-031 G B PF-033 G B PF-034 G B
PF-035 G B PF-036 G B PF-037 G B PF-040 G B PF-041 G B PF-042 G B
PF-043 G B PF-045 G B PF-046 G B PF-048 G B PF-049 G B PF-051 G B
PF-052 G B PF-053 G B PF-056 G B PF-057 G B PF-058 G B PF-061 G B
PF-063 G B PF-064 G B PF-065 G B PF-066 G B PF-067 G B PF-068 G B
PF-069 G B PF-070 G B PF-071 G B PF-073 G B PF-074 G B PF-075 G B
PF-076 G B PF-099 G B PF-123 G B PF-124 G B PF-125 G B PF-127 G B
PF-128 G B PF-129 G B PF-133 G B PF-135 G B PF-137 G B PF-139 G B
PF-140 G B PF-143 G B PF-144 G B PF-145 G B PF-148 G B M PF-149 G B
PF-153 G B PF-156 G B PF-157 G B PF-164 G B PF-168 G B M PF-171 G B
PF-173 G B PF-175 G B PF-176 G B PF-178 G B PF-180 G B PF-186 G B
PF-188 G B PF-190 G B PF-191 G B PF-192 G B PF-196 G B PF-203 G B
PF-204 G B PF-208 G B PF-209 G B M PF-212 G B PF-215 G B PF-224 G B
PF-226 G B PF-233 G B PF-234 G B PF-235 G B PF-249 G B PF-255 G B
PF-257 G B PF-270 G B PF-271 G B PF-273 G B PF-276 G B PF-278 G B M
PF-283 G B M PF-289 G B PF-292 G B PF-294 G B PF-297 G B PF-301 G B
PF-305 G B PF-306 G B PF-307 G B M PF-313 G B PF-319 G B PF-322 G M
PF-344 G B PF-347 G B PF-349 G B PF-350 G B PF-354 G B PF-355 G B
PF-356 G B PF-357 G B PF-360 G B PF-362 G B PF-363 G B PF-366 G B
PF-369 G B PF-370 G B PF-373 G B PF-374 G B PF-375 G B PF-376 G B
PF-378 G B PF-379 G B PF-380 G B PF-381 G B PF-382 G B PF-383 G B
PF-385 G B PF-386 G B PF-387 G B PF-389 G B PF-390 G B PF-392 G B
PF-393 G B PF-394 G B PF-395 G B PF-396 G B PF-397 G B PF-398 G B
PF-399 G B PF-401 G B PF-403 G B PF-404 G B PF-405 G B PF-406 G B
PF-407 G B PF-408 G B PF-410 G B PF-411 G B PF-413 G B PF-414 G B
PF-416 G B PF-417 G B PF-418 G B PF-421 G B PF-422 G B PF-423 G B
PF-424 G B PF-425 G B PF-426 G B PF-427 G B PF-428 G B PF-429 G B
PF-430 G B PF-431 G B PF-432 G B PF-433 G B PF-434 G B PF-437 G M
PF-439 G B PF-440 G B PF-442 G B PF-443 G B PF-444 G B PF-445 G B
PF-446 G B PF-447 G B PF-S003 G B PF-448 G B M PF-450 G B PF-451 G
B PF-452 G B PF-453 G B PF-454 G B PF-456 G B PF-457 G B PF-458 G B
PF-459 G B PF-460 G B PF-461 G B PF-462 G B PF-464 G B PF-465 G B
PF-466 G B PF-467 G B PF-469 G B PF-470 G B PF-471 G B PF-472 G B
PF-473 G B PF-474 G B PF-475 G B PF-476 G B PF-477 G B PF-478 G B
PF-479 G B PF-480 G B PF-482 G B PF-484 G B PF-497 B M PF-499 B M
PF-511 G B M PF-512 G B M PF-513 G B PF-514 G B PF-515 G B PF-516 G
PF-517 G B PF-518 G B PF-519 G B PF-520 G B M PF-521 G B M PF-522 G
B M
PF-523 B M PF-524 G B M PF-525 G M PF-526 G B PF-527 G B M PF-528 G
B PF-529 G B M PF-530 G M PF-531 G M PF-537 G B PF-538 G M PF-539 G
B PF-540 G B PF-542 G B PF-543 G B PF-544 G B PF-545 G B M PF-546 G
B PF-547 G B M PF-548 G B PF-549 G B PF-550 G B PF-551 G B PF-552 G
B PF-553 G B PF-554 G B PF-555 G B PF-556 G B PF-557 G B PF-558 G B
PF-559 G B PF-560 G B PF-562 G B PF-563 G B PF-564 G B PF-566 G B
PF-567 G B PF-569 G B PF-572 G B PF-573 G B PF-575 G B PF-576 G B
PF-577 G B PF-578 G B PF-580 G B PF-581 G B PF-583 G B M PF-584 G B
PF-585 G B PF-586 G B PF-587 G B PF-588 G B PF-589 G B PF-590 G B
PF-592 G B PF-593 G B PF-594 G B PF-595 G B PF-596 G B PF-597 G B
PF-598 G B PF-599 G B PF-600 G B M PF-601 G B PF-602 G B PF-603 G B
PF-604 G B PF-605 G B PF-606 G M PF-607 G B PF-609 G B PF-610 G B
PF-612 G B PF-613 G B PF-614 G B PF-615 G B PF-616 G B PF-617 G B
PF-619 G B PF-621 G B PF-622 G B PF-623 G B PF-625 G B PF-626 G B
PF-627 G B PF-629 G B PF-630 G B PF-631 G B PF-632 G B PF-634 G B
PF-635 G B PF-636 G B PF-637 G B PF-638 G B PF-639 G B PF-640 G B
PF-642 G B PF-655 G B PF-664 G B PF-672 G B M PF-681 G B PF-686 G B
PF-737 G B PF-738 G B PF-741 G B PF-744 G B PF-745 G B PF-746 G B
PF-748 G B PF-749 G B PF-752 G B PF-756 G B PF-757 G B PF-760 G B
PF-761 G B PF-762 G B PF-763 G B PF-764 G B PF-770 G B PF-776 G B
PF-C052 G B PF-C055 G B PF-C057 G B PF-C058 G B PF-C061 G B PF-C062
G B PF-C064 G B PF-C065 G B PF-C069 G B PF-C071 G B PF-C072 G B
PF-C075 G B PF-C084 G B PF-C085 G B PF-C086 G B PF-C088 G B PF-C091
G B PF-C095 G B PF-C098 G B PF-C120 G B PF-C131 G B PF-C135 G B
PF-C136 G B PF-C137 G B PF-C139 G B PF-C142 G B PF-C143 G B PF-C145
G B PF-C180 G B PF-C181 G B PF-C194 G B PF-C281 G B PF-C290 G B
PF-C291 G B B: targeting/binding activity; M: antimicrobial
activity; G: Growth or phenotype altering.
[0148] Other peptides believed to show binding, growth altering,
and/or antimicrobial activity are shown in Table 9.
TABLE-US-00009 TABLE 9 Additional peptides believed to have
binding, growth altering, and/or antimicrobial activity. ID
Sequence SEQ ID No. PF-198 RRLASRRSLVVST 1624 PF-227
RLLGLYGENSAAGFIASVIGAVIILFIYNLIARKS 1625 PF-260
GHLRVCWILWLQSANPLSFRHHYLAVMW 1626 PF-261
MDIWKFIKSFNTVNTYLLLSCVLLIILVLYFYVINPA 1627 PF-277
MIIQNKKIEKIYKYQTKEIFLNKTSLRAGFVFRMVRVLI 1628 PF-280
MLIDWQEPDIEKSFCAAFLKISVSVLVYRTPLGYGNQLRE 1629 PF-286 FFDGEVGCGC
1630 PF-287 ILEQNIEEVFFIQS 1631 PF-312
MDKIRIWNNFHISNEYIKQRYGIISIPLFYVYLF 1632 PF-321
FAKKNPCRMRVPNTGTWYLVVNQDGNSGIVNFSINTIQN 1633 PF-327
MLVFQMRYQMRYVDKTSTVLKQTKNSDYADK 1634 PF-330
MLMNFEVYQQRILIIYNKCYHLKAVGKNLQLFIIVD 1635 PF-331
MGRHLWNPSYFVATVSENTEEQIRKYINNQKKQVK 1636 PF-341 DDKNEGKIAQGEY 1637
PF-391 EASVYRE 1638 PF-420 MVKHNFDVTDKTGKISSKHCFEITDKTDVV 1639
PF-708 DRPSQTTHHTLSSSRITGPS 1640 PF-710 EALLPPDPPDEDSQRIIPQ 1641
PF-713 DRPSQTTHHTLSSSRITGPS 1642 PF-715 LEDTKALFPCFVPI 1643 PF-718
KKYSSFKSMIDDLEYDA 1644 PF-719 FKSMIDDLEYDA 1645 PF-721
TEQAKKIVDILNNWLE 1646 PF-722 STSPSVTSVYAEALGLK 1647 PF-723
VGAMAIFLNVVAMLAGV 1648 PF-725 ARTIQNNGCLIHNSRYP 1649 PF-726
CDDLYALEAQGTLNELLKK 1650 PF-729 TPEPVVIVKP 1651 PF-730
FEDIEQIIKYHLIDGKIVAPLLLDR 1652 PF-734 SDIIAEMFQQGELEPMLRDAVAA 1653
PF-736 KGSASGSASGSGSAK 1654 PF-739 KSGASSVASAAKSG 1655 PF-742
AAATTATTAK 1656 PF-743 TKGTTTGTAKTTGVTTGTAK 1657 PF-769
GSRGGAKRGGARG 1658 PF- WSESQPPTATPRPHAEVARAGLVTPPTL 1659 C031 PF-
QPIGFPTDSVHGTDLVHRLRGTTSSR 1660 C038 PF-
LENLDIEGLTEMKEHIEDLIAEKSAAESIEEVIVEAE 1661 C077 PF-
AYSLTFQNPNDNLTDEEVAKYMEKITKALTEKIGAEVR 1662 C205 PF-S016
PLTRETFAERGIRKARVARTFSEEEPPF 1663
III. Design and Construction of STAMPs and Other Chimeric
Constructs.
[0149] In various embodiments this invention provides chimeric
moieties comprising one or more targeting moieties attached to one
or more effectors. The targeting moieties can be selected to
preferentially bind to a target microorganism (e.g., bacteria,
virus, fungi, yeast, alga, protozoan, etc.) or group of
microorganisms (e.g., gram-negative or gram-positive bacteria,
particular genus, species, etc.) In certain embodiments the
targeting moiety comprises one or more novel microorganism-binding
peptides as described herein (see, e.g., Table 3, and/or Table 10,
and/or Table 12). In certain embodiments the targeting moiety
comprises non-peptide moieties (e.g., antibodies, receptor,
receptor ligand, lectin, and the like).
[0150] In various embodiments the effector comprises a moiety whose
activity is to be delivered to the target microorganism(s), to a
biofilm comprising the target microorganism(s), to a cell or tissue
comprising the target microorganism(s), and the like. In certain
embodiments the targeting moiety comprises one or more
antimicrobial peptide(s) as described herein (see, e.g., Tables 4,
5 and/or 14), an antibiotic (including, but not limited to a
steroid antibiotic), a detectable label, a porphyrin, a
photosensitizing agent, an epitope tag, a lipid or liposome, a
nanoparticle, a dendrimer, and the like.
[0151] In certain embodiments one or more targeting moieties are
attached to a single effector. In certain embodiments one or more
effectors are attached to a single targeting moiety. In certain
embodiments multiple targeting moieties are attached to multiple
effectors. The targeting moieties(s) can be attached directly to
the effector(s) or through a linker. Where the targeting moiety and
the effector comprise peptides the chimeric moiety can be a fusion
protein.
[0152] A) Targeting Moieties.
[0153] In various embodiments this invention provides targeting
moieties that preferentially and/or specifically bind to a
microorganism (e.g., a bacterium, a fungus, a yeast, etc.). One or
more such targeting moieties can be attached to one or more
effectors to provide chimeric moieties that are capable of
delivering the effector(s) to a target (e.g., a bacterium, a
fungus, a yeast, a biofilm comprising the bacterium or fungus or
yeast, etc.).
[0154] In various embodiments, targeting moieties include, but are
not limited to peptides that preferentially bind particular
microorganisms (e.g., bacteria, fungi, yeasts, protozoa, algae,
viruses, etc.) or groups of such microorganisms, e.g., as described
above, antibodies that bind particular microorganisms or groups of
microorganisms, receptor ligands that bind particular
microorganisms or groups of microorganisms, porphyrins (e.g.,
metalloporphyrins), lectins that bind particular microorganisms or
groups of microorganisms, and the like. As indicated it will be
appreciated that references to microorganisms or groups of
microorganism include bacteria or groups of bacteria, viruses or
groups of viruses, yeasts or groups of yeasts, protozoa or groups
of protozoa, viruses or groups of viruses, and the like.
[0155] i. Targeting Peptides.
[0156] In certain embodiments, the targeting moiety comprises one
or more targeting peptides that bind particular bacteria, fungi,
and/or yeasts, and/or algae, and/or viruses and/or that bind
particular groups of bacteria, and/or groups of fungi, and/or
groups of yeasts, and/or groups of algae.
[0157] In certain embodiments the targeting peptide can comprise
one or more domains capable of binding, specifically binding, or
preferentially binding to a microorganism, e.g., a target microbial
organism (see, e.g., Table 3). In certain embodiment, the targeting
peptide be identified via screening peptide libraries. For example,
a phage display peptide library can be screened against a target
microbial organism or a desired antigen or epitope thereof. Any
peptide identified through such screening can be used as a
targeting peptide for the target microbial organism. Illustrative
additional targeting peptides are shown in Table 10.
TABLE-US-00010 TABLE 10 Additional illustrative targeting moieties.
SEQ Targeting Moiety/ ID Organism Structure/sequence NO LPSB-1
RGLRRLGRRGLRRLGR 1664 Phob-1 KPVLPVLPVLPVL 1665 LPSB-2
VLRIIRIAVLRIIRIA 1666 LPTG-1 LPETGGSGGSLPETG 1667 .alpha.-1
RAHIRRAHIRR 1668 ANION-1 DEDEDDEEDDDEEE 1669 PHILIC-1
STMCGSTMCGSTMCG 1670 SA5.1/S. aureus VRLPLWLPSLNE 1671 SA5.3/S.
aureus ANYFLPPVLSSS 1672 SA5.4/S. aureus SHPWNAQRELSV 1673 SA5.5/S.
aureus SVSVGMRPMPRP 1674 SA5.6/S. aureus WTPLHPSTNRPP 1675 SA5.7/S.
aureus SVSVGMKPSPRP 1676 SA5.8/S. aureus SVSVGMKPSPRP 1677 SA5.9/S.
aureus SVPVGPYNESQP 1678 SA5.10/S. aureus WAPPLFRSSLFY 1679
SA2.2/S. aureus WAPPXPXSSLFY 1680 SA2.4/S. aureus HHGWTHHWPPPP 1681
SA2.5/S. aureus SYYSLPPIFHIP 1682 SA2.6/S. aureus HFQENPLSRGGEL
1683 SA2.7/S. aureus FSYSPTRAPLNM 1684 SA2.8/S. aureus SXPXXMKXSXXX
1685 SA2.9/S. aureus VSRHQSWHPHDL 1686 SA2.10/S. aureus
DYXYRGLPRXET 1687 SA2.11/S. aureus SVSVGMKPSPRP 1688 S.
aureus/Consensus V/Q/H-P/H-H-E-F/Y-K/H-H/A-L/H-X-X-K/R-P/L 1689
DH5.1/E coli. KHLQNRSTGYET 1690 DH5.2/E coli. HIHSLSPSKTWP 1691
DH5.3/E coli. TITPTDAEMPFL 1692 DH5.4/E coli. HLLESGVLERGM 1693
DH5.5/E coli. HDRYHIPPLQLH 1694 DH5.6/E coli. VNTLQNVRHMAA 1695
DH5.7/E coli. SNYMKLRAVSPF 1696 DH5.8/E coli. NLQMPYAWRTEF 1697
DH5.9/E coli. QKPLTGPHFSLI 1698 CSP/S. mutans SGSLSTFFRLFNRSFTQALGK
1699 CSPC18/S. mutans LSTFFRLFNRSFTQALGK 1700 CSPC16/S. mutans
TFFRLFNRSFTQALGK 1701 CSPM8/S. mutans TFFRLFNR 1702 KH/Pseudomonas
spp KKHRKHRKHRKH 1703 (US 2004/0137482) cCF10 LVTLVFV 1704 AgrD1
YSTCDFIM 1705 AgrD2 GVNACSSLF 1706 AgrD3 YINCDFLL 1707 NisinA
ITSISLCTPGCKTGALMGCNMRTATCIICSIIIVSK 1708 PlnA
KSSAYSLQMGATAIKQVKKLFKKWGW 1709 S3L1-5 WWYNWWQDW 1710 Penetratin
RQIKIWFWNRRMKWKK* 1711 Tat EHWSYCDLRPG 1712 Pep-1N KETWWETWWTEW
1713 Pep27 MRKEFHNVLSSGQLLADKRPARDYNRK 1714 HABP35
LKQKIKHVVKLKVVVKLRSQLVKRKQN 1715 HABP42 (all D) STMMSRSHKTRSHHV
1716 HABP52 GAHWQFNALTVRGGGS 1717 Hi3/17 KQRTSIRATEGCLPS 1718
.alpha.-E. coli peptide QEKIRVRLSA 1719 Salivary Receptor
QLKTADLPAGRDETTSFVLV* 1720 Adhesion Fragment S1 (Sushi frag.)
GFKLKGMARISCLPNGQWSNFPPKCIRECAMVSS 1721 (LPS binding) S3 (Sushi
frag.) HAEHKVKIGVEQKYGQFPQGTEVTYTCSGNYFLM 1722 (LPS binding) MArg.1
AMDMYSIEDRYFGGYAPEVG 1723 (Mycoplasma infected cell line binding
peptide BPI fragment 1 ASQQGTAALQKELKRIKPDYSDSFKIKH 1724 (LPS
binding) 6,376,462 BPI fragment 2
SSQISMVPNVGLKFSISNANIKISGKWKAQKRFLK 1725 (LPS binding) 6,376,462
BPI fragment 3 VHVHISKSKVGWLIQLFHKKIESALRNK 1726 (LPS binding)
6,376,462 LBP fragment 1 AAQEGLLALQSELLRITLPDFTGDLRIPH 1727 (LPS
binding) 6,376,462 LBP fragment 2
HSALRPVPGQGLSLSISDSSIRVQGRWKVRKSFFK 1728 (LPS binding) 6,376,462
LBP fragment 3 VEVDMSGDLGWLLNLFHNQIESKFQKV 1729 (LPS binding)
6,376,462 B. anthracis spore ATYPLPIR 1730 binding (WO/1999/036081)
Bacillus spore binding peptides of 5-12 amino acids containing the
sequence 1731 (WO/1999/036081) Asn-His-Phe-Leu peptides of 5-12
amino acids containing the sequence 1732 Asn-His-Phe-Leu-Pro
Thr-Ser-Glu-Asn-Val-Arg-Thr (TSQNVRT) 1733 A peptide of formula
Thr-Tyr-Pro-X-Pro-X-Arg 1734 (TYPXPXR) where X is a Ile, Val or
Leu. A peptide having the sequence TSQNVRT. 1735 A peptide having
the sequence TYPLPIR 1736 LPS binding peptide 1 TFRRLKWK 1737
(6,384,188) LPS BP 2 (6,384,188) RWKVRKSFFKLQ 1738 LPS BP 3
(6,384,188) KWKAQKRFLKMS 1739 Pseudomonas pilin KCTSDQDEQFIPKGCSK
1740 binding peptide (5,494,672) RNAII inhibiting YSPWTNF 1741
peptide (S. Aureus) Patents and patent publications disclosing the
referenced antibodies are identified in the table.
[0158] In certain embodiments the targeting moieties can comprise
other entities, particularly when utilized with an antimicrobial
peptide as described, for example, in Table 4. Illustrative
targeting moieties can include a polypeptide, a peptide, a small
molecule, a ligand, a receptor, an antibody, a protein, or portions
thereof that specifically interact with a target microbial
organism, e.g., the cell surface appendages such as flagella and
pili, and surface exposed proteins, lipids and polysaccharides of a
target microbial organism.
[0159] ii. Targeting Antibodies.
[0160] In certain embodiments the targeting moieties can comprise
one or more antibodies that bind specifically or preferentially a
microorganism or group of microorganisms (e.g., bacteria, fungi,
yeasts, protozoa, viruses, algae, etc.). The antibodies are
selected to bind an epitope characteristic or the particular target
microorganism(s). In various embodiments such epitopes or antigens
are typically is gram-positive or gram-negative specific, or
genus-specific, or species-specific, or strain specific and located
on the surface of a target microbial organism. The antibody that
binds the epitope or antigen can direct an anti-microbial peptide
moiety or other effector to the site. Furthermore, in certain
embodiments the antibody itself can provide anti-microbial activity
in addition to the activity provided by effector moiety since the
antibody may engage an immune system effector (e.g., a T-cell) and
thereby elicit an antibody-associated immune response, e.g., a
humoral immune response.
[0161] Antibodies that bind particular target microorganisms can be
made using any methods readily available to one skilled in the art.
For example, as described in U.S. Pat. No. 6,231,857 (incorporated
herein by reference) three monoclonal antibodies, i.e., SWLA1,
SWLA2, and SWLA3 have been made against S. mutans. Monoclonal
antibodies obtained from non-human animals to be used in a
targeting moiety can also be humanized by any means available in
the art to decrease their immunogenicity and increase their ability
to elicit anti-microbial immune response of a human. Illustrative
microorganisms and/or targets to which antibodies may be directed
are shown, for example, in Tables 3 and 11.
[0162] Various forms of antibody include, without limitation, whole
antibodies, antibody fragments (e.g., (Fab').sub.2 Fab', etc.),
single chain antibodies (e.g., scFv), minibodies, Di-miniantibody,
Tetra-miniantibody, (scFv).sub.2, Diabody, scDiabody, Triabody,
Tetrabody, Tandem diabody, VHH, nanobodies, affibodies, unibodies,
and the like.
[0163] Methods of making such antibodies are well known to those of
skill in the art. In various embodiments, such methods typically
involve providing the microorganism, or a component thereof for use
as an antigen to raise an immune response in an organism or for use
in a screening protocol (e.g., phage or yeast display).
[0164] For example, polyclonal antibodies are typically raised by
one or more injections (e.g. subcutaneous or intramuscular
injections) of the target microorganism(s) or components thereof
into a suitable non-human mammal (e.g., mouse, rabbit, rat,
etc.).
[0165] If desired, the immunizing microorganism or antigen derived
therefrom can be administered with or coupled to a carrier protein
by conjugation using techniques that are well-known in the art.
Such commonly used carriers which are chemically coupled to the
peptide include keyhole limpet hemocyanin (KLH), thyroglobulin,
bovine serum albumin (BSA), and tetanus toxoid. The coupled peptide
is then used to immunize the animal (e.g. a mouse or a rabbit).
[0166] The antibodies are then obtained from blood samples taken
from the mammal. The techniques used to develop polyclonal
antibodies are known in the art (see, e.g., Methods of Enzymology,
"Production of Antisera With Small Doses of Immunogen: Multiple
Intradermal Injections", Langone, et al. eds. (Acad. Press, 1981)).
Polyclonal antibodies produced by the animals can be further
purified, for example, by binding to and elution from a matrix to
which the peptide to which the antibodies were raised is bound.
Those of skill in the art will know of various techniques common in
the immunology arts for purification and/or concentration of
polyclonal antibodies, as well as monoclonal antibodies see, for
example, Coligan, et al. (1991) Unit 9, Current Protocols in
Immunology, Wiley Interscience).
[0167] In certain embodiments the antibodies produced will be
monoclonal antibodies ("mAb's"). The general method used for
production of hybridomas secreting mAbs is well known (Kohler and
Milstein (1975) Nature, 256:495
[0168] Antibody fragments, e.g. single chain antibodies (scFv or
others), can also be produced/selected using phage display and/or
yeast display technology. The ability to express antibody fragments
on the surface of viruses that infect bacteria (bacteriophage or
phage) or yeasts makes it possible to isolate a single binding
antibody fragment, e.g., from a library of greater than 10.sup.10
nonbinding clones. To express antibody fragments on the surface of
phage (phage display) or yeast, an antibody fragment gene is
inserted into the gene encoding a phage surface protein (e.g.,
pIII) and the antibody fragment-pIII fusion protein is displayed on
the phage surface (McCafferty et al. (1990) Nature, 348: 552-554;
Hoogenboom et al. (1991) Nucleic Acids Res. 19: 4133-4137).
[0169] Since the antibody fragments on the surface of the phage or
yeast are functional, phage bearing antigen binding antibody
fragments can be separated from non-binding phage by antigen
affinity chromatography (McCafferty et al. (1990) Nature, 348:
552-554). Depending on the affinity of the antibody fragment,
enrichment factors of 20 fold-1,000,000 fold are obtained for a
single round of affinity selection.
[0170] Human antibodies can be produced without prior immunization
by displaying very large and diverse V-gene repertoires on phage
(Marks et al. (1991) J. Mol. Biol. 222: 581-597.
[0171] In certain embodiments, nanobodies can be used as targeting
moieties. Methods of making V.sub.hH (nanobodies) are also well
known to those of skill in the art. The Camelidae heavy chain
antibodies are found as homodimers of a single heavy chain,
dimerized via their constant regions. The variable domains of these
camelidae heavy chain antibodies are referred to as V.sub.HH
domains or V.sub.HH, and can be either used per se as nanobodies
and/or as a starting point for obtaining nanobodies. Isolated
V.sub.HH retain the ability to bind antigen with high specificity
(see, e.g., Hamers-Casterman et al. (1993) Nature 363: 446-448). In
certain embodiments such V.sub.HH domains, or nucleotide sequences
encoding them, can be derived from antibodies raised in Camelidae
species, for example in camel, dromedary, llama, alpaca and
guanaco. Other species besides Camelidae (e.g. shark, pufferfish)
can produce functional antigen-binding heavy chain antibodies, from
which (nucleotide sequences encoding) such naturally occurring
V.sub.HH can be obtained, e.g. using the methods described in U.S.
Patent Publication US 2006/0211088.
[0172] In various embodiments, for use in therapy, human proteins
are preferred, primarily because they are not as likely to provoke
an immune response when administered to a patient. Comparisons of
camelid V.sub.HH with the V.sub.H domains of human antibodies
reveals several key differences in the framework regions of the
camelid V.sub.HH domain corresponding to the V.sub.H/V.sub.L
interface of the human V.sub.H domains. Mutation of these human
residues to V.sub.HH resembling residues has been performed to
produce "camelized" human V.sub.H domains that retain antigen
binding activity, yet have improved expression and solubility.
[0173] Libraries of single V.sub.H domains have also been derived
for example from V.sub.H genes amplified from genomic DNA or from
mRNA from the spleens of immunized mice and expressed in E. coli
(Ward et al. (1989) Nature 341: 544-546) and similar approaches can
be performed using the V.sub.H domains and/or the V.sub.L domains
described herein. The isolated single VH domains are called "dAbs"
or domain antibodies. A "dAb" is an antibody single variable domain
(V.sub.H or V.sub.L) polypeptide that specifically binds antigen. A
"dAb" binds antigen independently of other V domains; however, as
the term is used herein, a "dAb" can be present in a homo- or
heteromultimer with other V.sub.H or V.sub.L domains where the
other domains are not required for antigen binding by the dAb,
i.e., where the dAb binds antigen independently of the additional
V.sub.H or V.sub.L domains.
[0174] As described in U.S. Patent Publication US 2006/0211088
methods are known for the cloning and direct screening of
immunoglobulin sequences (including but not limited to multivalent
polypeptides comprising: two or more variable domains--or antigen
binding domains--and in particular V.sub.H domains or V.sub.HH
domains; fragments of V.sub.L, V.sub.H or V.sub.HH domains, such as
CDR regions, for example CDR3 regions; antigen-binding fragments of
conventional 4-chain antibodies such as Fab fragments and scFv's,
heavy chain antibodies and domain antibodies; and in particular of
V.sub.H sequences, and more in particular of V.sub.HH sequences)
that can be used as part of and/or to construct such
nanobodies.
[0175] Methods and procedures for the production of VHH/nanobodies
can also be found for example in WO 94/04678, WO 96/34103, WO
97/49805, WO 97/49805 WO 94/25591, WO 00/43507 WO 01/90190, WO
03/025020, WO 04/062551, WO 04/041863, WO 04/041865, WO 04/041862,
WO 04/041867, PCT/BE2004/000159, Hamers-Casterman et al. (1993)
Nature 363: 446; Riechmann and Muyldermans (1999) J. Immunological
Meth., 231: 25-38; Vu et al. (1997) Molecular Immunology,
34(16-17): 1121-1131; Nguyen et al. (2000) EMBO J., 19(5): 921-930;
Arbabi Ghahroudi et al. (19997) FEBS Letters 414: 521-526; van der
Linden et al. (2000) J. Immunological Meth., 240: 185-195;
Muyldermans (2001) Rev. Molecular Biotechnology 74: 277-302; Nguyen
et al. (2001) Adv. Immunol. 79: 261, and the like.
[0176] In certain embodiments the antibody targeting moiety is a
unibody. Unibodies provide an antibody technology that produces a
stable, smaller antibody format with an anticipated longer
therapeutic window than certain small antibody formats. In certain
embodiments unibodies are produced from IgG4 antibodies by
eliminating the hinge region of the antibody. Unlike the full size
IgG4 antibody, the half molecule fragment is very stable and is
termed a uniBody. Halving the IgG4 molecule left only one area on
the UniBody that can bind to a target. Methods of producing
unibodies are described in detail in PCT Publication WO2007/059782,
which is incorporated herein by reference in its entirety (see,
also, Kolfschoten et al. (2007) Science 317: 1554-1557).
[0177] Affibody molecules are class of affinity proteins based on a
58-amino acid residue protein domain, derived from one of the
IgG-binding domains of staphylococcal protein A. This three helix
bundle domain has been used as a scaffold for the construction of
combinatorial phagemid libraries, from which Affibody variants that
target the desired molecules can be selected using phage display
technology (see, e.g., Nord et al. (1997) Nat. Biotechnol. 15:
772-777; Ronmark et al. (2002) Eur. J. Biochem., 269: 2647-2655.).
Details of Affibodies and methods of production are known to those
of skill (see, e.g., U.S. Pat. No. 5,831,012 which is incorporated
herein by reference in its entirety).
[0178] It will also be recognized that antibodies can be prepared
by any of a number of commercial services (e.g., Berkeley antibody
laboratories, Bethyl Laboratories, Anawa, Eurogenetec, etc.).
[0179] Illustrative antibodies that bind various microorganisms are
shown in Table 11.
Table 11. Illustrative Antibodies that Bind Target
Microorganisms.
TABLE-US-00011 TABLE 11 Illustrative antibodies that bind target
microorganisms. Source Antibody U.S. Pat. No. 7,195,763
Polyclonal/monoclonal binds specific Gram(+) cell wall repeats U.S.
Pat. No. 6,939,543 Antibodies against G(+) LTA U.S. Pat. No.
7,169,903 Antibodies against G(+) peptidoglycan U.S. Pat. No.
6,231,857 Antibody against S. mutans (Shi) U.S. Pat. No. 5,484,591
Gram(-) binding antibodies US 2007/0231321 Diabody binding to
Streptococcus surface antigen I/II US 2003/0124635 Antibody against
S. mutans US 2006/0127372 Antibodies to Actinomyces naeslundii,
Lactobacillus casei US 2003/0092086 Antibody to S. sobrinus U.S.
Pat. No. 7,364,738 Monoclonal antibodies to the ClfA protein in S.
aureus U.S. Pat. No. 7,632,502 Antibodies against C. albicans U.S.
Pat. No. 7,608,265 Monoclonal against C. difficile U.S. Pat. No.
4,777,136 Monoclonal Antibodies against Pseudomonas aeruginosa see,
e.g., ab20429, ab20560, Antibody against S. pneumoniae ab79522,
ab35165, ab65602 from AbCAMm Cambridge Science Park, U.K.
[0180] In addition, antibodies (targeting moieties) that bind other
microorganisms can readily be produced using, for example, the
methods described above.
[0181] iii. Porphyrins.
[0182] In certain embodiments porphyrins, or other photosensitizing
agents, can be used as targeting moieties in the constructs
described herein. In particular, metalloporphyrins, particularly a
number of non-iron metalloporphyrins mimic heme in their molecular
structure and are actively accumulated by bacteria via high
affinity heme-uptake systems. The same uptake systems can be used
to deliver antibiotic-porphyrin and antibacterial-porphyrin
conjugates. Illustrative targeting porphyrins suitable for this
purpose are described in U.S. Pat. No. 6,066,628 and shown herein,
for example, in FIGS. 1 and 2.
[0183] For example, certain artificial (non-iron) metalloporphyrins
(MPs) (Ga-IX, Mn-IX,) are active against Gram-negative and
Gram-positive bacteria and acid-fast bacilli (e.g., Y.
enterocolitica, N. meningitides, S. marcescens, E. coli, P.
mirabills, K. pneumoniae, K. oxytoca, Ps. aeruginosa, C. freundii,
E. aerogenes, F. menigosepticum, S. aureus, B. subtilis, S.
pyogenes A, E. faecalis, M. smegmatis, M. bovis, M. tuber., S.
crevisiae) as described in Tables 1-5 of U.S. Pat. No. 6,066,628.
These MPs can be used as targeting moieties against these
microorganisms.
[0184] Similarly, some MPs are also growth-inhibitory against
yeasts, indicating their usefulness targeting moieties to target
Candida species (e.g., Candida albicans, C. krusei, C. pillosus, C.
glabrata, etc.) and other mycoses including but not limited to
those caused by as Trichophyton, Epidermophyton, Histoplasma,
Aspergillus, Cryptococcus, and the like.
[0185] Porphyrins, and other photosensitizers, also have
antimicrobial activity. Accordingly, in certain embodiments, the
porphyrins, or other photosensitizers, can be used as effectors
(e.g., attached to targeting peptides as described herein). In
various embodiments the porphyrins or other photosensitizers can
provide a dual functionality, e.g., as a targeting moiety and an
antimicrobial and can be attached to a targeting peptide and/or to
an antimicrobial peptide as described herein.
[0186] Illustrative porphyrins and other photosensitizers are shown
in FIGS. 1-11 and described in more detail in the discussion of
effectors below.
[0187] iv. Pheromones.
[0188] In certain embodiments, pheromones from microorganisms can
be used as targeting moieties. Illustrative pheromones from
bacteria and fungi are shown in Table 12.
TABLE-US-00012 TABLE 12 Illustrative bacterial and fungal
pheromones utilizable as targeting moieties. Locus tag Product
Sequence SEQ ID Bacterial Pheromones gi|1041118|dbj|BAA11198.1|
iPD1 [Enterococcus MKQQKKHIAALLF 1742 faecalis] ALILTLVS
gi|1113947|gb|AAB35253.1| iAM373sex pheromone SIFTLVA 1743 inhibito
[Enterococcus faecalis, Peptide, 7 aa]
gi|115412|sp|P13268.1|CAD1_ENTFA Sex pheromone CAD1 LFSLVLAG 1744
gi|116406|sp|P11932.1|CIA_ENTFA Sex pheromone cAM373 AIFILAS 1745
(Clumping-inducing agent) (CIA) gi|117240|sp|P13269.1|CPD1_ENTFA
Sex pheromone cPD1 FLVMFLSG 1746
gi|12056953|gb|AAG48144.1|AF322594_1 putative peptide
DSIRDVSPTFNKIRR 1747 pheromone PrcA WFDGLFK [Lactobacillus
paracasei] gi|123988|sp|P24803.1|IAD1_ENTFA Sex pheromone inhibitor
MSKRAMKKIIPLIT 1748 determinant precursor LFVVTLVG (iAD1)
gi|126362994|emb|CAM35812.1| precursor of pheromone KDEIYWKPS 1749
peptide ComX [Bacillus amyloliquefaciens FZB42]
gi|1587088|prf||2205353A pheromone YSTCDFIM 1750
gi|15900442|ref|NP_345046.1| peptide pheromone BlpC GLWEDLLYNINRY
1751 [Streptococcus AHYIT pneumoniae TIGR4]
gi|1617436|emb|CAA66791.1| competence pheromone DIRHRINNSIWRDIF
1752 [Streptococcus gordonii] LKRK gi|1617440|emb|CAA66786.1|
competence pheromone DVRSNKIRLWWEN 1753 [Streptococcus gordonii]
IFFNKK gi|18307870|gb|AAL67728.1|AF456134_2 ComX pheromone PTTREWDG
1754 precursor [Bacillus mojavensis]
gi|18307874|gb|AAL67731.1|AF456135_2 ComX pheromone LQIYTNGNWVPS
1755 precursor [Bacillus mojavensis] gi|29377808|ref|NP_816936.1|
sex pheromone inhibitor MSKRAMKKIIPLIT 1756 determinant
[Enterococcus LFVVTLVG faecalis V583] gi|3342125|gb|AAC27522.1|
putative pheromone GAGKNLIYGMGYG 1757 [Enterococcus faecium]
YLRSCNRL gi|41018893|sp|P60242.1|CSP1_STRPN Competence-stimulating
EMRLSKFFRDFILQ 1758 peptide type 1 precursor RKK (CSP-1)
gi|57489126|gb|AAW51333.1| PcfP [Enterococcus WSEIEINTKQSN 1759
faecalis] gi|57489152|gb|AAW51349.1| PrgT [Enterococcus HISKERFEAY
1760 faecalis] gi|58616083|ref|YP_195761.1| UvaF [Enterococcus
KYKCSWCKRVYTL 1761 faecalis] RKDHRTAR gi|58616111|ref|YP_195802.1|
PcfP [Enterococcus WSEIEINTKQSN 1762 faecalis]
gi|58616132|ref|YP_195769.1| PrgQ [Enterococcus MKTTLKKLSRYIA 1763
faecalis] VVIAITLIFI gi|58616137|ref|YP_195772.1| PrgT
[Enterococcus HISKERFEAY 1764 faecalis]
gi|6919848|sp|O33689.1|CSP_STROR Competence-stimulating
DKRLPYFFKHLFSN 1765 peptide precursor (CSP) RTK
gi|6919849|sp|O33666.1|CSP2_STRMT Competence-stimulating
EMRKPDGALFNLF 1766 peptide precursor (CSP) RRR
gi|6919850|sp|O33668.1|CSP3_STRMT Competence-stimulating
EMRKSNNNFFHFL 1767 peptide precursor (CSP) RRI
gi|6919851|sp|O33672.1|CSP1_STRMT Competence-stimulating
ESRLPKIRFDFIFPR 1768 peptide precursor (CSP) KK
gi|6919852|sp|O33675.1|CSP4_STRMT Competence-stimulating
EIRQTHNIFFNFFKRR 1769 peptide precursor (CSP)
gi|6919853|sp|O33690.1|CSP2_STROR Competence-stimulating
DWRISETIRNLIFPR 1770 peptide precursor (CSP) RK
gi|999344|gb|AAB34501.1| cOB1bacterial sex VAVLVLGA 1771 pheromone
[Enterococcus faecalis, Peptide, 8 aa]
gi|18307878|gb|AAL67734.1|AF456136_2 ComX pheromone FFEDDKRKSFI
1772 precursor [Bacillus subtilis]
gi|18307882|gb|AAL67737.1|AF456137_2 ComX pheromone FFEDDKRKSFI
1773 precursor [Bacillus subtilis] gi|28272731|emb|CAD65660.1|
accessory gene regulator MKQKMYEAIAHLF 1774 protein D, peptide
KYVGAKQLVMCC pheromone precursor VGIWFETKIPDELRK [Lactobacillus
plantarum WCFS1] gi|28379890|ref|NP_786782.1| accessory gene
regulator MKQKMYEAIAHLF 1775 protein D, peptide KYVGAKQLVMCC
pheromone precursor VGIWFETKIPDELRK [Lactobacillus plantarum WCFS1]
gi|57489105|gb|AAW51312.1| PrgF [Enterococcus VVAYVITQVGAIRF 1776
faecalis] gi|58616090|ref|YP_195779.1| PrgF [Enterococcus
VVAYVITQVGAIRF 1777 faecalis] gi|58616138|ref|YP_195762.1| PrgN
[Enterococcus LLKLQDDYLLHLE 1778 faecalis] RHRRTKKIIDEN
gi|57489117|gb|AAW51324.1| PcfF [Enterococcus EDIKDLTDKVQSLN 1779
faecalis] ALVQSELNKLIKRK DQS gi|57489119|gb|AAW51326.1| PcfH
[Enterococcus WFLDFSDWLSKVP 1780 faecalis] SKLWAE
gi|58616102|ref|YP_195792.1| PcfF [Enterococcus EDIKDLTDKVQSLN 1781
faecalis] ALVQSELNKLIKRK DQS gi|58616104|ref|YP_195794.1| PcfH
[Enterococcus WFLDFSDWLSKVP 1782 faecalis] SKLWAE Fungi
gi|1127585|gb|AAA99765.1| mfa1 gene product MLSIFAQTTQTSAS 1783
EPQQSPTAPQGRDN GSPIGYSSCVVA gi|1127592|gb|AAA99771.1| mfa2 gene
product MLSIFETVAAAAPV 1784 TVAETQQASNNEN RGQPGYYCLIA
gi|11907715|gb|AAG41298.1| pheromone precursor PSLPSSPPSLLPPLPL
1785 MFalpha1D LKLLATRRPTLVG [Cryptococcus neoformans MTLCV var.
neoformans] gi|13810235|emb|CAC37424.1| M-factor precursor Mfm1
MDSMANSVSSSSV 1786 [Schizosaccharomyces VNAGNKPAETLNK pombe]
TVKNYTPKVPYMC VIA gi|14269436|gb|AAK58071.1|AF378295_1 peptide
mating pheromone MDTFTYVDLAAVA 1787 precursor Bbp2-3 AAAVADEVPRDFE
[Schizophyllum DQITDYQSYCIIC commune]
gi|14269440|gb|AAK58073.1|AF378297_1 peptide mating pheromone
SNVHGWCVVA 1788 precursor Bbp2-1 [Schizophyllum commune]
gi|1813600|gb|AAB41859.1| pheromone precursor NTTAHGWCVVA 1789
Bbp1(1) [Schizophyllum commune] gi|24940428|emb|CAD56313.1|
a-pheromone MQPSTVTAAPKDK 1790 [Saccharomyces TSAEKKDNYIIKGV
paradoxus] FWDPACVIA gi|27549492|gb|AAO17258.1| pheromone phb3.1
GPTWWCVNA 1791 [Coprinopsis cinerea] gi|27549494|gb|AAO17259.1|
pheromone phb3.2 SGPTWFCIIQ 1792 [Coprinopsis cinerea]
gi|27752314|gb|AAO19469.1| pheromone protein a FTAIFSTLSSSVASK 1793
pecursor [Cryptococcus TDAPRNEEAYSSG neoformans var. grubii] NSP
gi|2865510|gb|AAC02682.1| MAT-1 pheromone MFSIFAQPAQTSVS 1794
[Ustilago hordei] ETQESPANHGANP GKSGSGLGYSTCV VA
gi|3023372|sp|P78742.1|BB11_SCHCO RecName: Full = Mating-
NTTAHGWCVVA 1795 type pheromone BBP1(1); Flags: Precursor
gi|3025079|sp|P56508.1|SNA2_YEAST RecName: Full = Protein SDDNYGSLA
1796 SNA2 gi|37626077|gb|AAQ96360.1| pheromone precursor Phb3
NGLTFWCVIA 1797 B5 [Coprinopsis cinerea] gi|37626081|gb|AAQ96362.1|
pheromone precursor PSWFCVIA 1798 Phb3.2 B45 [Coprinopsis cinerea]
gi|37626083|gb|AAQ96363.1| pheromone precursor ASWFCTIA 1799 Phb3.1
B47 [Coprinopsis cinerea] gi|37961432|gb|AAP57503.1| Ste3-like
pheromone PHHKIANASDKRR 1800 receptor [Thanatephorus RMYFEIFMCAVL
cucumeris] gi|400250|sp|P31962.1|MFA1_USTMA RecName: Full = A1-
MLSIFAQTTQTSAS 1801 specific pheromone; EPQQSPTAPQGRDN AltName:
Full = Mating GSPIGYSSCVVA factor A1
gi|400251|sp|P31963.1|MFA2_USTMA RecName: Full = A2- MLSIFETVAAAAPV
1802 specific pheromone; TVAETQQASNNEN AltName: Full = Mating
RGQPGYYCLIA factor A2 gi|41209131|gb|AAR99617.1| lipopeptide mating
SLTYAWCVVA 1803 pheromone precursor Bap2(3) [Schizophyllum commune]
gi|41209146|gb|AAR99650.1| lipopeptide mating TSMAHAWCVVA 1804
pheromone precursor Bap3(2) [Schizophyllum commune]
gi|41209149|gb|AAR99653.1| lipopeptide mating GYCVVA 1805 pheromone
precursor Bbp2(8) [Schizophyllum commune]
gi|46098187|gb|EAK83420.1| MFA1_USTMA A1- MLSIFAQTTQTSAS 1806
SPECIFIC PHEROMONE EPQQSPTAPQGRDN (MATING FACTOR A1) GSPIGYSSCVVA
[Ustilago maydis 521] gi|546861|gb|AAB30833.1| M-factor mating
MDSMANTVSSSVV 1807 pheromone NTGNKPSETLNKT [Schizosaccharomyces
VKNYTPKVPYMCV pombe] IA gi|5917793|gb|AAD56043.1|AF184069_1
pheromone Mfa2 MFSLFETVAAAVK 1808 [Ustilago hordei] VVSAAEPEHAPTNE
GKGEPAPYCIIA gi|6014618|gb|AAF01424.1|AF186389_1 Phb3.2.42
[Coprinus LTWFCVIA 1809 cinereus] gi|68266363|gb|AAY88882.1|
putative pheromone LREKRRRRWFEAF 1810 receptor STE3.4 MGFGL
[Coprinellus disseminatus] gi|71012805|ref|XP_758529.1| A1-specific
pheromone MLSIFAQTTQTSAS 1811 [Ustilago maydis 521] EPQQSPTAPQGRDN
GSPIGYSSCVVA gi|72414834|emb|CAI59748.1| mating factor a1.3
MDALTLFAPVSLG 1812 [Sporisorium reilianum] AVATEQAPVDEER
PNRQTFPWIGCVVA gi|72414854|emb|CAI59758.1| mating factor a2.1
MFIFESVVASVQAV 1813 [Sporisorium reilianum] SVAEQDQTPVSEG
RGKPAVYCTIA gi|1127587|gb|AAA99767.1| rba1 gene product
PWMSLLFSFLALLA 1814 LILPKLSKDDPLGL TRQPR
gi|151941959|gb|EDN60315.1| pheromone-regulated ASISLIMEGSANIEA
1815 membrane protein VGKLVWLAAALPL [Saccharomyces cerevisiae AFI
YJM789] gi|3025095|sp|Q07549.1|SNA4_YEAST Protein SNA4
ARNVYPSVETPLLQ 1816 GAAPHDNKQSLVE SPPPYVP
gi|73921293|sp|Q08245.3|ZEO1_YEAST RecName: Full = Protein
FLKKLNRKIASIFN 1817 ZEO1; AltName: Full = Zeocin resistance protein
1 gi|74644573|sp|Q9P305.3|IGO2_YEAST RecName: Full = Protein
DSISRQGSISSGPPP 1818 EDF (E. coli) IGO2 RSPNK NNWNN 1819
[0189] v. Targeting Enhancers/Opsonins
[0190] In certain embodiments compositions are contemplated that
incorporate a targeting enhancer (e.g., an opsonin) along with one
or more targeting moieties (e.g., targeting peptides). Targeting
enhancers include moieties that increase binding affinity, and/or
binding specificity, and/or internalization of a moiety by the
target cell/microorganism.
[0191] Accordingly, in certain embodiments, a targeting moiety
and/or a targeted antimicrobial molecule comprise a peptide, with
the desired level of binding specificity and/or avidity, attached
(e.g., conjugated) to an opsonin. When bound to a target cell
through the targeting peptide, the opsonin component encourages
phagocytosis and destruction by resident macrophages, dendritic
cells, monocytes, or PMNs. Opsonins contemplated for conjugation
can be of a direct or indirect type.
[0192] Direct opsonins include, fore example, any bacterial surface
antigen, PAMP (pathogen-associated molecular pattern), or other
molecule recognized by host PRRs (pathogen recognizing receptors).
Opsonins can include, but are not limited to, bacterial protein,
lipid, nucleic acid, carbohydrate and/or oligosaccharide
moieties.
[0193] In certain embodiments opsonins include, but are not limited
to, N-acetyl-D-glucosamine (GlcNAc), N-acetyl-D-galactosamine
(GlaNAc), N-acetylglucosamine-containing muramyl peptides,
NAG-muramyl peptides, NAG-NAM, peptidoglycan, teichoic acid,
lipoteichoic acid, LPS, o-antigen, mannose, fucose, ManNAc,
galactose, maltose, glucose, glucosamine, sucrose, mannosamine,
galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, or
alpha-1,3-gal-gal, or other sugars.
[0194] In certain embodiments, opsonins include indirect opsonins.
Indirect opsonins function through binding to a direct opsonin
already present. For example an Fc portion of an antibody, a
sugar-binding lectin protein (example MBL), or host complement
factors (example C3b, C4b, iC3b).
[0195] In certain embodiments the opsonin is to
galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, or
alpha-1,3-gal-gal.
[0196] Other examples of opsonin molecules include, but are not
limited to antibodies (e.g., IgG and IgA), components of the
complement system (e.g., C3b, C4b, and iC3b), mannose-binding
lectin (MBL) (initiates the formation of C3b), and the like.
[0197] Methods of coupling an opsonin to a targeting moiety are
well known to those of skill in the art (see, e.g., discussion
below regarding attachment of effectors to targeting moieties).
[0198] B) Effectors.
[0199] Any of a wide number of effectors can be coupled to
targeting moieties as described herein to preferentially deliver
the effector to a target organism and/or tissue. Illustrative
effectors include, but are not limited to detectable labels, small
molecule antibiotics, antimicrobial peptides, porphyrins or other
photosensitizers, epitope tags/antibodies for use in a pretargeting
protocol, agents that physically disrupt the extracellular matrix
within a community of microorganisms, microparticles and/or
microcapsules, nanoparticles and/or nanocapsules, "carrier"
vehicles including, but not limited to lipids, liposomes,
dendrimers, cholic acid-based peptide mimics or other peptide
mimics, steroid antibiotics, and the like.
[0200] i. Detectable Labels.
[0201] In certain embodiments chimeric moieties are provided
comprising a targeting moiety (e.g., as described in Table 3)
attached directly or through a linker to a detectable label. Such
chimeric moieties are effective for detecting the presence and/or
quantity, and/or location of the microorganism(s) to which the
targeting moiety is directed. Similarly these chimeric moieties are
useful to identify cells and/or tissues and/or food stuffs and/or
other compositions that are infected with the targeted
microorganism(s).
[0202] Detectable labels suitable for use in such chimeric moieties
include any composition detectable by spectroscopic, photochemical,
biochemical, immunochemical, electrical, optical, or chemical
means. Illustrative useful labels include, but are not limited to,
biotin for staining with labeled streptavidin conjugates, avidin or
streptavidin for labeling with biotin conjugates fluorescent dyes
(e.g., fluorescein, texas red, rhodamine, green fluorescent
protein, and the like, see, e.g., Molecular Probes, Eugene, Oreg.,
USA), radiolabels (e.g., .sup.3H, .sup.125I, .sup.35S, .sup.14C,
.sup.32P, .sup.99Tc, .sup.203Pb, .sup.67Ga, .sup.68Ga, .sup.72As,
.sup.111In, .sup.113mIn, .sup.97Ru, .sup.62Cu, 641Cu, .sup.52Fe,
.sup.52mMn, .sup.51Cr, .sup.186Re, .sup.188Re, .sup.77As, .sup.90Y,
.sup.67Cu, .sup.169Er, .sup.121Sn, .sup.127Te, .sup.142Pr,
.sup.143Pr, .sup.198Au, .sup.199Au, .sup.161Tb, .sup.109Pd,
.sup.165Dy, .sup.149Pm, .sup.151Pm, .sup.153Sm, .sup.157Gd,
.sup.159Gd, .sup.166Ho, .sup.172Tm, .sup.169Yb, .sup.175Yb,
.sup.177Lu, .sup.105Rh, .sup.111Ag, and the like), enzymes (e.g.,
horse radish peroxidase, alkaline phosphatase and others commonly
used in an ELISA), various colorimetric labels, magnetic or
paramagnetic labels (e.g., magnetic and/or paramagnetic
nanoparticles), spin labels, radio-opaque labels, and the like.
Patents teaching the use of such labels include, for example, U.S.
Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437;
4,275,149; and 4,366,241.
[0203] It will be recognized that fluorescent labels are not to be
limited to single species organic molecules, but include inorganic
molecules, multi-molecular mixtures of organic and/or inorganic
molecules, crystals, heteropolymers, and the like. Thus, for
example, CdSe--CdS core-shell nanocrystals enclosed in a silica
shell can be easily derivatized for coupling to a biological
molecule (Bruchez et al. (1998) Science, 281: 2013-2016).
Similarly, highly fluorescent quantum dots (zinc sulfide-capped
cadmium selenide) have been covalently coupled to biomolecules for
use in ultrasensitive biological detection (Warren and Nie (1998)
Science, 281: 2016-2018).
[0204] In various embodiments spin labels are provided by reporter
molecules with an unpaired electron spin which can be detected by
electron spin resonance (ESR) spectroscopy. Illustrative spin
labels include organic free radicals, transitional metal complexes,
particularly vanadium, copper, iron, and manganese, and the like.
Exemplary spin labels include, for example, nitroxide free
radicals.
[0205] Means of detecting such labels are well known to those of
skill in the art. Thus, for example, where the label is a
radioactive label, means for detection include a scintillation
counter or photographic film as in autoradiography. Where the label
is a fluorescent label, it may be detected by exciting the
fluorochrome with the appropriate wavelength of light and detecting
the resulting fluorescence, e.g., by microscopy, visual inspection,
via photographic film, by the use of electronic detectors such as
charge coupled devices (CCDs) or photomultipliers and the like.
Similarly, enzymatic labels may be detected by providing
appropriate substrates for the enzyme and detecting the resulting
reaction product. Finally, simple colorimetric labels may be
detected simply by observing the color associated with the
label.
[0206] ii. Antibiotics.
[0207] In certain embodiments chimeric moieties are provided
comprising a targeting moiety (e.g. as described in Table 3)
attached directly or through a linker to a small molecule
antibiotic and/or to a carrier (e.g., a lipid or liposome, a
polymer, etc.) comprising a small molecule antibiotic. Illustrative
antibiotics are shown in Table 13.
TABLE-US-00013 TABLE 13 Illustrative antibiotics for use in the
chimeric moieties described herein. Class Generic Name BRAND NAME
Aminoglycosides Amikacin AMIKIN .RTM. Gentamicin GARAMYCIN .RTM.
Kanamycin KANTREX .RTM. Neomycin Netilmicin NETROMYCIN .RTM.
Streptomycin Tobramycin NEBCIN .RTM. Paromomycin HUMATIN .RTM.
Carbacephem Loracarbef LORABID .RTM. Carbapenems Ertapenem INVANZ
.RTM. Doripenem FINIBAX .RTM. Imipenem/Cilastatin PRIMAXIN .RTM.
Meropenem MERREM .RTM. Cephalosporins Cefadroxil DURICEF .RTM.
(First generation) Cefazolin ANCEF .RTM. Cefalotin or Cefalothin
KEFLIN .RTM. Cefalexin KEFLEX .RTM. Cephalosporins Cefaclor CECLOR
.RTM. (Second Cefamandole MANDOLE .RTM. generation) Cefoxitin
MEFOXIN .RTM. Cefprozil CEFZIL .RTM. Cefuroxime CEFTIN, ZINNAT
.RTM. Cephalosporins Cefixime SUPRAX .RTM. (Third Cefdinir OMNICEF
.RTM. generation) Cefditoren SPECTRACEF .RTM. Cefoperazone CEFOBID
.RTM. Cefotaxime CLAFORAN .RTM. Cefpodoxime Ceftazidime FORTAZ
.RTM. Ceftibuten CEDAX .RTM. Ceftizoxime Ceftriaxone ROCEPHIN .RTM.
Cephalosporins Cefepime MAXIPIME .RTM. (Fourth generation)
Cephalosporins Ceftobiprole (Fifth generation) Glycopeptides
Teicoplanin Vancomycin VANCOCIN .RTM. Macrolides Azithromycin
Zithromax Clarithromycin Biaxin Dirithromycin Erythromycin
Erythocin, Erythroped Roxithromycin Troleandomycin Telithromycin
Ketek Monobactams Aztreonam Penicillins Amoxicillin NOVAMOX .RTM.,
AMOXIL .RTM. Ampicillin Azlocillin Carbenicillin Cloxacillin
Dicloxacillin Flucloxacillin FLOXAPEN .RTM. Mezlocillin Meticillin
Nafcillin Oxacillin Penicillin Piperacillin Ticarcillin
Polypeptides Bacitracin Colistin Polymyxin B Quinolones Mafenide
Prontosil (archaic) Sulfacetamide Sulfamethizole Sulfanilimide
(archaic) Sulfasalazine Sulfisoxazole Trimethoprim BACTRIM .RTM.
Trimethoprim- Sulfamethoxazole (Co- trimoxazole) (TMP-SMX)
Tetracyclines Demeclocycline Doxycycline VIBRAMYCIN .RTM.
Minocycline MINOCIN .RTM. Oxytetracycline TERRACIN .RTM.
Tetracycline SUMYCIN .RTM. Natural products Antimicrobial herbal
extracts Essential oils Farnesol Licorice root extracts
Glycyrrhizol A Glycyrrhizol B 6,8-diisoprenyl-5,7,4'-
trihydroxyisoflavone Others Arsphenamine SALVARSAN .RTM.
Chloramphenicol CHLOROMYCETIN .RTM. Clindamycin CLEOCIN .RTM.
Lincomycin Ethambutol Fosfomycin Fusidic acid FUCIDIN .RTM.
Furazolidone Isoniazid Linezolid ZYVOX .RTM. Metronidazole FLAGYL
.RTM. Mupirocin BACTROBAN .RTM. Nitrofurantoin MACRODANTIN .RTM.,
MACROBID .RTM. Platensimycin Pyrazinamide Quinupristin/ SYNCERCID
.RTM. Dalfopristin Rifampin or Rifampicin Tinidazole Artemisinin
Antifungals Amphotericin B Anidulafungin Caspofungin acetate
Clotrimazole Fluconazole Flucytosine Griseofulvin Itraconazole
Ketoconazole Micafungin Miconazole Nystatin Pentamidine
Posaconazole Terbinafine Voriconazole Antimycobiotics
Aminosalicylic Acid Capreomycin Clofazimine Cycloserine Ethionamide
Rifabutin Rifapentine Antivirals Abacavir Acyclovir Adefovir
Amantadine Atazanavir Cidofovir Darunavir Didanosine Docosanol
Efavirenz Emtricitabine Enfuvirtide Entecavir Etravirine
Famciclovir Fomivirsen Fosamprenavir Foscarnet Ganciclovir
Idoxuridine Indinavir Interferon alpha Lamivudine
Lopinavir/ritonavir Maraviroc Nelfinavir Nevirapine Oseltamivir
Penciclovir Peramivir Raltegravir Ribavirin Rimantadine Ritonavir
Saquinavir Stavudine Telbivudine Tenofovir Tipranavir Trifluridine
Valacyclovir Valganciclovir Zanamivir Zidovudine Anti-parasitics
Albendazole Artesunate Atovaquone Bephenium hydroxynaphthoate
Chloroquine Dapsone Diethyl-carbamazine Diloxanide furoate
Eflornithine Emetine HCl Furazolidone Ivermectin Lindane
Mebendazole Mefloquine Melarsoprol Miltefosine Niclosamide
Nifurtimox Nitazoxanide Oxamniquine Paromomycin Permethrin
Piperazine Praziquantel Primaquine Pyrantel pamoate Pyrimethamine
Proguanil Quinacrine HCl Quinidine Quinine Sodium Stibogluconate
Spiramycin Thiabendazole Tinidazole
[0208] iii. Porphyrins and Non-Porphyrin Photosensitizers.
[0209] In certain embodiments, porphyrins and other
photosensitizers can be used as targeting moieties and/or as
effectors in the methods and compositions of this invention. A
photosensitizer is a drug or other chemical that increases
photosensitivity of the organism (e.g., bacterium, yeast, fungus,
etc.). As targeting moieties the photosensitizers (e.g.,
porphyrins) are preferentially uptaken by the target microorganisms
and thereby facilitate delivery of the chimeric moiety to the
target microorganism.
[0210] As effectors, photosensitizers can be useful in photodynamic
antimicrobial chemotherapy (PACT). In various embodiments PACT
utilizes photosensitizers and light (e.g., visible, ultraviolet,
infrared, etc.) in order to give a phototoxic response in the
target organism(s), often via oxidative damage.
[0211] Currently, the major use of PACT is in the disinfection of
blood products, particularly for viral inactivation, although more
clinically-based protocols are used, e.g. in the treatment of oral
infection or topical infection. The technique has been shown to be
effective in vitro against bacteria (including drug-resistant
strains), yeasts, viruses, parasites, and the like.
[0212] Attaching a targeting moiety (e.g., a targeting peptide) to
the photosensitizer, e.g., as described herein, provides a means of
specifically or preferentially targeting the photosensitizer(s) to
particular species or strains(s) of microorganism.
[0213] A wide range of photosensitizers, both natural and synthetic
are known to those of skill in the art (see, e.g., Wainwright
(1998) J. Antimicrob. Chemotherap. 42: 13-28). Photosensitizers are
available with differing physicochemical make-up and
light-absorption properties. In various embodiments
photosensitizers are usually aromatic molecules that are efficient
in the formation of long-lived triplet excited states. In terms of
the energy absorbed by the aromatic-system, this again depends on
the molecular structure involved. For example, furocoumarin
photosensitizers (psoralens) absorb relatively high energy
ultraviolet (UV) light (c. 300-350 nm), whereas macrocyclic,
heteroaromatic molecules such as the phthalocyanines absorb lower
energy, near-infrared light.
[0214] Illustrative photosensitizers include, but are not limited
to porphyrinic macrocyles (especially porphyrins, chlorines, etc.,
see, e.g., FIGS. 1 and 2). In particular, metalloporphyrins,
particularly a number of non-iron metalloporphyrins mimic haem in
their molecular structure and are actively accumulated by bacteria
via high affinity haem-uptake systems. The same uptake systems can
be used to deliver antibiotic-porphyrin and antibacterial-porphyrin
conjugates. Illustrative targeting porphyrins suitable for this
purpose are described in U.S. Pat. No. 6,066,628 and shown herein
in FIGS. 1 and 2.
[0215] Illustrative examples of targeted porphyrins are described
in Example 5 and associated figures and in FIG. 13.
[0216] For example, certain artificial (non-iron) metalloporphyrins
(MPs) (Ga-IX, Mn-IX,) are active against Gram-negative and
Gram-positive bacteria and acid-fast bacilli (e.g., Y.
enterocolitica, N. meningitides, S. marcescens, E. coli, P.
mirabills, K. pneumoniae, K. oxytoca, Ps. aeruginosa, C. freundii,
E. aerogenes, F. menigosepticum, S. aureus, B. subtilis, S.
pyogenes A, E. faecalis, M. smegmatis, M. bovis, M. tuber., S.
crevisiae) as described in Tables 1-5 of U.S. Pat. No. 6,066,628.
These MPs can be used as targeting moieties against these
microorganisms.
[0217] Similarly, some MPs are also growth-inhibitory against
yeasts, indicating their usefulness targeting moieties to target
Candida species (e.g., Candida albicans, C. krusei, C. pillosus, C.
glabrata, etc.) and other mycoses including but not limited to
those caused by as Trichophyton, Epidermophyton, Histoplasma,
Aspergillus, Cryptococcus, and the like.
[0218] Other photosensitizers include, but are not limited to
cyanines (see, e.g., FIG. 6) and phthalocyanines (see, e.g., FIG.
4), azines (see, e.g., FIG. 5) including especially methylene blue
and touidine blue, hypericin (see, e.g., FIG. 8), acridines (see,
e.g., FIG. 9) including especially Rose Bengal (see, e.g., FIG.
10), crown ethers (see, e.g., FIG. 11), and the like. In certain
embodiments, the photosensitizers include tin chlorin 6 and related
compounds (e.g., other chlorines and tin porphyrins).
[0219] Another light-activated compound is cucumin (see, FIG.
12).
[0220] In certain embodiments the photosensitizers are toxic or
growth inhibitors without light activation. For example, some
non-iron metalloporphyrins (MPs) (see, e.g., FIGS. 1 and 2 herein)
possess a powerful light-independent antimicrobial activity. In
addition, haemin, the most well known natural porphyrin, possesses
a significant antibacterial activity that can augmented by the
presence of physiological concentrations of hydrogen peroxide or a
reducing agent.
[0221] Typically, when activated by light, the toxicity or growth
inhibition effect is substantially increased. Typically, they
generate radical species that affect anything within proximity. In
certain embodiments to get the best selectivity from targeted
photosensitizers, anti-oxidants can be used to quench un-bound
photosensitizers, limiting the damage only to cells where the
conjugates have accumulated due to the targeting peptide. The
membrane structures of the target cell act as the proton donors in
this case.
[0222] In typical photodynamic antimicrobial chemotherapy (PACT)
the targeted photosensitizer is "activated by the application of a
light source (e.g., a visible light source, an ultraviolate light
source, an infrared light source, etc.). PACT applications however
need not be limited to topical use. Regions of the mouth, throat,
nose, sinuses are readily illuminated. Similarly regions of the gut
can readily be illuminated using endoscopic techniques. Other
internal regions can be illumined using laparoscopic methods or
during other surgical procedures. For example, in certain
embodiments involving the insertion or repair or replacement of an
implantable device (e.g., a prosthetic device) it contemplated that
the device can be coated or otherwise contacted with a chimeric
moiety comprising a targeting moiety attached to a photosensitizer
as described herein. During the surgical procedure and/or just
before closing, the device can be illuminated with an appropriate
light source to activate the photosensitizer.
[0223] The targeted photosensitizers and uses thereof described
herein are illustrative and not to be limiting. Using the teachings
provided herein, other targeted photosensitizers and uses thereof
will be available to one of skill in the art.
[0224] iv. Antimicrobial Peptides.
[0225] In certain embodiments, the effector can comprise one or
more antimicrobial peptides or compound antimicrobial peptides,
e.g., as described above. Numerous antimicrobial peptides are well
known to those of skill in the art.
[0226] In certain embodiments the antimicrobial peptides comprise
one or more amino acid sequences described above (e.g., one or more
domains comprising amino acid sequences in Tables 4 and/or 5)
and/or one or more of the amino acid sequences shown in Table 14.
In certain embodiments the antimicrobial peptides comprise one or
more amino acid sequences described in the "Collection of
Anti-Microbial Peptides" (CAMP) an online database developed for
advancement the understanding of antimicrobial peptides (see, e.g.,
Thomas et al. (2009) Nucleic Acids Research, 2009,
1-7.doi:10.1093/nar/gkp1021) available at
www.bicnirrh.res.in/antimicrobial.
TABLE-US-00014 TABLE 14 Other illustrative antimicrobial peptides.
AP numbers refer to ID in antimicrobial peptide database
(http://aps.unmc.edu/AP/main.php). SEQ ID Effector
Structure/Sequence No AP00274 1BH4, Circulin A
GIPCGESCVWIPCISAALGCSCKNK 1820 (CirA, plant VCYRN cyclotides, XXC,
ZZHp) AP00036 1BNB, Beta- DFASCHTNGGICLPNRCPGHMIQIG 1821 defensin 1
(cow) ICFRPRVKCCRSW AP00047 1BNB, Bovine GPLSCGRNGGVCIPIRCPVPMRQIG
1822 neutrophil beta- TCFGRPVKCCRSW defensin 12 (BNBD-12, cow)
AP00428 1C01, MiAMP1 SAFTVWSGPGCNNRAERYSKCGCS 1823 (Macadamia
AIHQKGGYDFSYTGQTAALYNQA integrifolia GCSGVAHTRFGSSARACNPFGWKS
antimicrobial IFIQC peptide 1, plant) AP00154 1CIX, Tachystatin
YSRCQLQGFNCVVRSYGLPTIPCC 1824 A2 (Horseshoe RGLTCRSYFPGSTYGRCQRY
crabs, Crustacea, BBS) AP00145 1CW5, VNYGNGVSCSKTKCSVNWGQAFQ 1825
Carnobacteriocin ERYTAGINSFVSGVASGAGSIGRRP B2 (CnbB2, class IIA
bacteriocin, bacteria) AP00153 1CZ6, Androctonin
RSVCRQIKICRRRGGCYYKCTNRPY 1826 (scorpions) AP00152 1D6X,
Tritrpticin VRRFPWWWPFLRR 1827 (synthetic) AP00201 1D7N, Mastoparan
INLKALAALAKKIL 1828 (insect) AP00140 1D9J, CecropinA-
KWKLFKKIGIGKFLHSAKKF 1829 Magainin2 hybrid (synthetic) AP00178
1DFN, human DCYCRIPACIAGERRYGTCIYQGRL 1830 alpha Defensin WAFCC
HNP-3 (human neutrophil peptide- 3, HNP3, human defensin, ZZHh)
AP01153 1DQC, Tachycitin YLAFRCGRYSPCLDDGPNVNLYSC 1831 (horseshoe
crabs, CSFYNCHKCLARLENCPKGLHYN Crustacea, BBS) AYLKVCDWPSKAGCT
AP00437 1DUM, Magainin 2 GIGKYLHSAKKFGKAWVGEIMNS 1832 analog
(synthetic) AP00451 1E4S, Human beta DHYNCVSSGGQCLYSACPIFTKIQG 1833
defensin 1 (HBD-1, TCYRGKAKCCK human defensin) AP00149 1EWS, Rabbit
MPCSCKKYCDPWEVIDGSCGLFNS 1834 kidney defensin 1 KYICCREK (RK-1)
AP00141 1F0E, CecropinA- KWKLFKKIPKFLHSAKKF 1835 Magainin2 Hybrid
(P18, synthetic) AP00142 1F0G, CecropinA- KLKLFKKIGIGKFLHSAKKF 1836
Magainin2 Hybrid (synthetic) AP00143 1F0H, CecropinA-
KAKLFKKIGIGKFLHSAKKF 1837 Magainin2 Hybrid (synthetic) AP00524
1FD4, Human beta GIGDPVTCLKSGAICHPVFCPRRYK 1838 defensin 2 (HBD-2,
QIGTCGLPGTKCCKKP human defensin, ZZHh) AP00438 1FJN, Mussel
GFGCPNNYQCHRHCKSIPGRCGGY 1839 Defensin MGD-1 CGGWHRLPCTCYRCG
AP00155 1FRY, SMAP-29 RGLRRLGRKIAHGVKKYGPTVLRII 1840 (SMAP29, sheep
RIAG cathelicidin) AP00150 1G89, Indolicidin ILPWKWPWWPWRR 1841
(cow cathelicidin, BBN, ZZHa) AP00156 1GR4, Microcin
VGIGTPISFYGGGAGHVPEYF 1842 J25, linear (MccJ25, bacteriocin,
bacteria) AP00151 1HR1, Indolicidin ILAWKWAWWAWRR 1843 P to A
mutant (synthetic) AP00196 1HU5, Ovispirin-1 KNLRRIIRKIIHIIKKYG
1844 (synthetic) AP00197 1HU6, Novispirin KNLRRIIRKGIHIIKKYG 1845
G10 (synthetic) AP00198 1HU7, Novispirin KNLRRITRKIIHIIKKYG 1846 T7
(synthetic) AP00445 1HVZ, Monkey GFCRCLCRRGVCRCICTR 1847 RTD-1
(rhesus theta-defensin-1, minidefensin-1, animal defensin, XXC,
BBS, lectin, ZZHa) AP00103 1i2v, Heliomicin DKLIGSCVWGAVNYTSDCNGECL
1848 variant (Hel-LL, LRGYKGGHCGSFANVNCWCET synthetic) AP00216
1ICA, Phormia ATCDLLSGTGINHSACAAHCLLRG 1849 defensin A (insect
NRGGYCNGKGVCVCRN defensin A) AP01224 1Jo3, Gramicidin B
VGALAVVVWLFLWLW 1850 (bacteria) AP01225 1jo4, Gramicidin C
VGALAVVVWLYLWLW 1851 (bacteria) AP00191 1KFP, Gomesin
ECRRLCYKQRCVTYCRGR 1852 (Gm, Spider, XXA) AP00283 1KJ6, Huamn beta
GIINTLQKYYCRVRGGRCAVLSCL 1853 defensin 3 (HBD-3,
PKEEQIGKCSTRGRKCCRRKK human defensin, ZZHh) AP00147 1KV4, Moricin
AKIPIKAIKTVGKAVGKGLRAINIA 1854 (insect, silk moth)
STANDVFNFLKPKKRKA AP00227 1L4V, Sapecin ATCDLLSGTGINHSACAAHCLLRG
1855 (insect, flesh fly) NRGGYCNGKAVCVCRN AP01161 1L9L, Human
GRDYRTCLTIVQKLKKMVDKPTQ 1856 granulysin RSVSNAATRVCTRGRSRWRDVCR
(huGran) NFMRRYQSRVIQGLVAGETAQQIC EDLRLCIPSTGPL AP00026 1LFC,
FKCRRWQWRMKKLGAPSITCVRR 1857 Lactoferricin B AF (LfcinB, cow, ZZHa)
AP00193 1M4F, human DTHFPICIFCCGCCHRSKCGMCCKT 1858 LEAP-1 (Hepcidin
25) AP00499 1MAG, Gramicidin VGALAVVVWLWLWLW 1859 A (gA, bacteria)
AP00403 1MM0, Termicin ACNFQSCWATCQAQHSIYFRRAFC 1860 (termite
defensin, DRSQCKCVFVRG insect defensin) AP00194 1MMC, Ac-AMP2
VGECVRGRCPSGMCCSQFGYCGK 1861 (plant defensin, GPKYCGR BBS) AP01206
1MQZ, Mersacidin CTFTLPGGGGVCTLTSECIC 1862 (bacteria) AP00429 1NKL,
Porcine GYFCESCRKIIQKLEDMVGPQPNE 1863 NK-Lysin (pig)
DTVTQAASQVCDKLKILRGLCKKI MRSFLRRISWDILTGKKPQAICVDI KICKE AP00633
1og7, Sakacin P/ KYYGNGVHCGKHSCTVDWGTAIG 1864 Sakacin 674 (SakP,
NIGNNAAANWATGGNAGWNK class IIA bacteriocin, bacteria) AP00195 1PG1,
Protegrin 1 RGGRLCYCRRRFCVCVGR 1865 (Protegrin-1, PG-1, pig
cathelicidin, XXA, ZZHa, BBBm) AP00928 1PXQ, Subtilosin
NKGCATCSIGAACLVDGPIPDFEIA 1866 A (XXC, class I GATGLFGLWG
bacteriocin, Gram- positive bacteria) AP00480 1Q71, Microcin
VGIGTPIFSYGGGAGHVPEYF 1867 J25 (cyclic MccJ25, class I microcins,
bacteriocins, Gram- negative bacteria, XXC; BBP) AP00211 1RKK,
RRWCFRVCYRGFCYRKCR 1868 Polyphemusin I (crabs, Crustacea) AP00430
1T51, IsCT ILGKIWEGIKSLF 1869 (Scorpion) AP00731 1ut3, Spheniscin-2
SFGLCRLRRGFCARGRCRFPSIPIGR 1870 (Sphe-2, penguin CSRFVQCCRRVW
defensin, avian defensin) AP00013 1VM5, Aurein 1.2 GLFDIIKKIAESF
1871 (frog) AP00214 1WO1, KWCFRVCYRGICYRRCR 1872 Tachyplesin I
(crabs, Crustacea, XXA, ZZHa) AP00644 1xc0, Pardaxin 4
GFFALIPKIISSPLFKTLLSAVGSALS 1873 (Pardaxin P-4, SSGGQE Pardaxin P4,
Pa4, flat fish) AP00493 1XKM, Distinctin NLVSGLIEARKYLEQLHRKLKNCKV
1874 (two chains for stability and transport? frog) AP00420 1XV3,
Penaeidin- HSSGYTRPLRKPSRPIFIRPIGCDVC 1875 4d (penaeidin 4,
YGIPSSTARLCCFRYGDCCHL shrimp, Crustacea) AP00035 1YTR, Plantaricin
KSSAYSLQMGATAIKQVKKLFKK 1876 A (PlnA, WGW
bacteriocin, bacteria) AP00166 1Z64, Pleurocidin
GWGSFFKKAAHVGKHVGKAALT 1877 (fish) HYL AP00780 1Z6V, Human
GRRRRSVQWCAVSQPEATKCFQW 1878 lactoferricin
QRNMRKVRGPPVSCIKRDSPIQCIQA AP00549 1ZFU, Plectasin
GFGCNGPWDEDDMQCHNHCKSIK 1879 (fungi, fungal GYKGGYCAKGGFVCKCY
defensin) AP00177 1ZMH, human CYCRIPACIAGERRYGTCIYQGRL 1880 alpha
Defensin WAFCC HNP-2 (human neutrophil peptide- 2, HNP2, human
defensin, ZZHh) AP00179 1ZMM, human VCSCRLVFCRRTELRVGNCLIGGV 1881
alpha Defensin SFTYCCTRVD HNP-4 (human neutrophil peptide- 4, HNP4,
human defensin) AP00180 1ZMP, human QARATCYCRTGRCATRESLSGVCE 1882
alpha Defensin ISGRLYRLCCR HD-5 (HD5, human defensin) AP00181 1ZMQ,
human STRAFTCHCRRSCYSTEYSYGTCT 1883 alpha Defensin VMGINHRFCCL HD-6
(HD6, human defensin) AP00399 1ZRW, Spinigerin
HVDKKVADKVLLLKQLRIMRLLT 1884 (insect, termite) RL AP01157 1ZRX,
Stomoxyn RGFRKHFNKLVKKVKHTISETAHV 1885 (insect) AKDTAVIAGSGAAVVAAT
AP00637 2A2B, Curvacin A/ ARSYGNGVYCNNKKCWVNRGEA 1886 sakacin A
(CurA, TQSIIGGMISGWASGLAGM SakA, class IIA bacteriocin, bacteria)
AP00558 2B68, Cg-Def GFGCPGNQLKCNNHCKSISCRAGY 1887 (Crassostrea
gigas CDAATLWLRCTCTDCNGKK defensin, oyster defensin, animal
defensin) AP01154 2B9K, LCI AIKLVQSPNGNFAASFVLDGTKWI 1888
(bacteria) FKSKYYDSSKGYWVGIYEVWDRK AP01005 2DCV, Tachystatin
YVSCLFRGARCRVYSGRSCCFGYY 1889 B1 (BBS, CRRDFPGSIFGTCSRRNF horseshoe
crabs) AP01006 2DCW, YITCLFRGARCRVYSGRSCCFGYY 1890 Tachystatin B1
CRRDFPGSIFGTCSRRNF (BBS, horseshoe crabs) AP00275 2ERI, Circulin B
CGESCVFIPCISTLLGCSCKNKVCY 1891 (CirB, plant RNGVIP cyclotides, XXC,
ZZHp) AP00707 2f3a, LLAA (LL- RLFDKIRQVIRKF 1892 37-derived aurein
1.2 analog, retro- FK13, synthetic) AP00708 2fbs, FK-13 (FK13,
FKRIVQRIKDFLR 1893 NMR-discovered LL-37 core peptide, XXA, ZZHs,
synthetic) AP00088 2G9L, Gaegurin-4 GILDTLKQFAKGVGKDLVKGAAQ 1894
(Gaegurin 4, frog) GVLSTVSCKLAKTC AP01011 2G9P, Latarcin 2a
GLFGKLIKKFGRKAISYAVKKARG 1895 (Ltc2a, BBM, KH spider) AP00612 2GDL,
Fowlicidin- LVQRGRFGRFLRKIRRFRPKVTITI 1896 2 (chCATH-2, bird
QGSARFG cathelicidin, chicken cathelicidin, BBL) AP00402 2GL1, VrD2
KTCENLANTYRGPCFTTGSCDDHC 1897 (Vigna radiata
KNKEHLRSGRCRDDFRCWCTRNC defensin 2, plant defensin, mung bean)
AP00285 2GW9, Cryptdin-4 GLLCYCRKGHCKRGERVRGTCGIR 1898 (Crp4,
animal FLYCCPRR defensin, alpha, mouse) AP00613 2hfr, Fowlicidin-3
RVKRFWPLVPVAINTVAAGINLYK 1899 (chCATH-3, bird AIRRK cathelicidin,
chicken cathelicidin) AP01007 2JMY, CM15 KWKLFKKIGAVLKVL 1900
(Synthetic) AP00728 2jni, Arenicin-2 RWCVYAYVRIRGVLVRYRRCW 1901
(marine polychaeta, BBBm) AP00473 2jos, Piscidin 1
FFHHIFRGIVHVGKTIHRLVTG 1902 (fish) AP01151 2JPJ, Lactococcin
GTWDDIGQGIGRVAYWVGKALGN 1903 G-a (chain a, class LSDVNQASRINRKKKH
IIb bacteriocin, bacteria. For chain b, see info) AP00757 2jpy,
Phylloseptin- FLSLIPHAINAVSTLVHHF 1904 H2 (PLS-H2, Phylloseptin-2,
PS- 2) (XXA, frog) AP00546 2jq0, Phylloseptin- FLSLIPHAINAVSAIAKHN
1905 1 (Phylloseptin-H1, PLS-H1, PS-1, XXA, frog) AP00758 2jq1,
Phylloseptin- FLSLIPHAINAVSALANHG 1906 3 (Phylloseptin-H3, PLS-H3,
PS-3) (XXA, frog) AP00727 2jsb, Arenicin-1 RWCVYAYVRVRGVLVRYRRCW
1907 (marine polychaeta, BBBm) AP00592 2k10, Ranatuerin-
GILSSFKGVAKGVAKDLAGKLLET 1908 2CSa (frog) LKCKITGC AP00485 2K38,
Cupiennin GFGALFKFLAKKVAKTVAKQAAK 1909 1a (spider) QGAKYVVNKQME
AP00310 2K6O, Human LL- LLGDFFRKSKEKIGKEFKRIVQRIK 1910 37 (LL37,
human DFLRNLVPRTES cathelicidin; released by proteinase 3 from its
precursor in neutrophils; FALL- 39; BBB, BBM, BBP, BBW, BBD, BBL,
ZZHh) AP00199 2LEU, Leucocin A KYYGNGVHCTKSGCSVNWGEAFS 1911 (LeuA,
class IIa AGVHRLANGGNGFW bacteriocin, bacteria) AP00144 2MAG,
Magainin 2 GIGKFLHSAKKFGKAFVGEIMNS 1912 (frog) AP00146 2MLT,
Melittin GIGAVLKVLTTGLPALISWIKRKRQQ 1913 (insect, ZZHa) AP01010
2PCO, Latarcin 1 SMWSGMWRRKLKKLRNALKKKL 1914 (Ltc1, BBM, KGEK
spider) AP00176 2PM1, human ACYCRIPACIAGERRYGTCIYQGRL 1915 alpha
Defensin WAFCC HNP-1 (human neutrophil peptide- 1, HNP1, human
defensin, ZZHh) AP01158 2RLG, RP-1 ALYKKFKKKLLKSLKRL 1916
(synthetic) AP00102 8TFV, Thanatin GSKKPVPIIYCNRRTGKCQRM 1917
(insect) AP00995 A58718, Carnocin GSEIQPR 1918 UI49 (bacteria)
AP01002 AAC18827, KSWSLCTPGCARTGSFNSYCC 1919 Mutacin III (mutacin
1140, bacteria) AP00987 ABI74601, Arasin SRWPSPGRPRPFPGRPKPIFRPRPCN
1920 1 (Crustacea) CYAPPCPCDRW AP01000 CAA63706,
GSGVIPTISHECHMNSFQFVFTCCS 1921 variacin (lantibiotic, class I
bacteriocin, bacteria) AP00361 O15946, Lebocin 4
DLRFWNPREKLPLPTLPPFNPKPIYI 1922 (insect, silk moth) DMGNRY AP00343
O16825, Andropin VFIDILDKMENAIHKAAQAGIGIAK 1923 (insect, fruit fly)
PIEKMILPK AP00417 O17513, SIGTAVKKAVPIAKKVGKVAIPIAK 1924
Ceratotoxin D AVLSVVGQLVG (insect, fly) AP00435 O18494, Styelin C
GWFGKAFRSVSNFYKKHKTYIHA 1925 (sea squirt, GLSAATLL tunicate, XXA)
AP00330 O18495, Styelin D GWLRKAAKSVGKFYYKHKYYIKA 1926 (Sea squirt,
AWQIGKHAL tunicate, XXA) AP00331 O18495, Styelin E
GWLRKAAKSVGKFYYKHKYYIKA 1927 (Sea squirt, AWKIGRHAL tunicate, XXA)
AP01001 O54329, Mutacin II NRWWQGVVPTVSYECRMNSWQH 1928
(lantibiotic, VFTCC mutacin H-29B, J- T8, class I bacteriocin,
bacteria) AP00342 O81338, AKCIKNGKGCREDQGPPFCCSGFC 1929
Antimicrobial YRQVGWARGYCKNR peptide 1 (plant) AP00373 O96059,
Moricin 2 AKIPIKAIKTVGKAVGKGLRAINIA 1930 (insect) STANDVFNFLKPKKRKH
AP00449 P01190, SYSMEHFRWGKPV 1931 Melanotropin alpha (Alpha-MSH)
AP00187 P01376, VVCACRRALCLPRERRAGFCRIRG 1932
CORTICOSTATIN RIHPLCCRR III (MCP-1, rabbit neutrophil peptide 1,
NP-1) (animal defensin, alpha- defensin, rabbit) AP00188 P01377,
VVCACRRALCLPLERRAGFCRIRG 1933 CORTICOSTATIN RIHPLCCRR IV (MCP-2,
rabbit neutrophil defensin 2, NP-2, animal defensin, rabbit)
AP00049 P01505, Bombinin GIGALSAKGALKGLAKGLAEHFAN 1934 (toad)
AP00139 P01507, Cecropin KWKLFKKIEKVGQNIRDGIIKAGP 1935 A (insect,
ZZHa) AVAVVGQATQIAK AP00128 P01509, Cecropin
KWKIFKKIEKVGRNIRNGIIKAGPA 1936 B (insect, silk VAVLGEAKAL moth)
AP00131 P01511, Cecropin WNPFKELERAGQRVRDAIISAGPA 1937 D (insect,
moth) VATVAQATALAK AP00136 P01518, Crabrolin FLPLILRKIVTAL 1938
(insect, XXA) AP00183 P04142, Cecropin RWKIFKKIEKMGRNIRDGIVKAGP
1939 B (insect) AIEVLGSAKAI AP00448 P04205, INLKAIAALAKKLL 1940
Mastoparan M (MP-M, insect, XXA) AP00234 P06833,
SDEKASPDKHHRFSLSRYAKLANR 1941 Seminalplasmin
LANPKLLETFLSKWIGDRGNRSV (SPLN, calcium transporter inhibitor,
caltrin, cow) AP00314 P07466, Rabbit VFCTCRGFLCGSGERASGSCTINGV 1942
neutrophil peptide RHTLCCRR 5 (NP-5, animal defensin, alpha-
defensin) AP00189 P07467, Rabbit VSCTCRRFSCGFGERASGSCTVNG 1943
neutrophil peptide VRHTLCCRR 4 (NP-4) AP00186 P07468,
GRCVCRKQLLCSYRERRIGDCKIR 1944 CORTICOSTATIN GVRFPFCCPR II (Rabbit
neutrophil peptide 3b (NP-3b, rabbit) AP00185 P07469,
ICACRRRFCPNSERFSGYCRVNGA 1945 CORTICOSTATIN RYVRCCSRR I (rabbit)
AP00217 P07469, Rabbit GICACRRRFCPNSERFSGYCRVNG 1946 neutrophil
defensin ARYVRCCSRR 3a (NP-3a, animal defensin, alpha- defensin)
AP00067 P07493, SKITDILAKLGKVLAHV 1947 Bombolitin II (insect, bee)
AP00068 P07494, IKIMDILAKLGKVLAHV 1948 Bombolitin III (insect, bee)
AP00069 P07495, INIKDILAKLVKVLGHV 1949 Bombolitin IV (insect, bee)
AP00070 P07496, INVLGILGLLGKALSHL 1950 Bombolitin V (insect, bee)
AP00236 P07504, Pyrularia KSCCRNTWARNCYNVCRLPGTISR 1951 thionin
(Pp-TH, EICAKKCDCKIISGTTCPSDYPK plant) AP00230 P08375, Sarcotoxin
GWLKKIGKKIERVGQHTRDATIQG 1952 IA (insect, flesh LGIAQQAANVAATAR
AP00231 P08376, Sarcotoxin GWLKKIGKKIERVGQHTRDATIQV 1953 IB
(insect, flesh IGVAQQAANVAATAR AP00232 P08377, Sarcotoxin
GWLRKIGKKIERVGQHTRDATIQV 1954 IC (insect, flesh LGIAQQAANVAATAR
AP00066 P10521, IKITTMLAKLGKVLAHV 1955 Bombolitin I (insect, bee)
AP00206 P10946, Lantibiotic WKSESLCTPGCVTGALQTCFLQTL 1956 subtilin
(class I TCNCKISK bacteriocin, bacteria) AP00312 P11477, Cryptdin-2
LRDLVCYCRARGCKGRERMNGTC 1957 (Crp2, animal RKGHLLYMLCCR defensin,
alpha, mouse) AP00205 P13068, Nisin A ITSISLCTPGCKTGALMGCNMKTA 1958
(lantibiotic, class I TCHCSIHVSK bacteriocin, bacteria) AP00215
P14214, RWCFRVCYRGICYRKCR 1959 Tachyplesin II (crabs, Crustacea)
AP00212 P14216, RRWCFRVCYKGFCYRKCR 1960 Polyphemusin II (crabs,
Crustacea, XXA, ZZHa. Derivatives: T22) AP00134 P14661, Cecropin
SWLSKTAKKLENSAKKRISEGIAIA 1961 P1 (pig) IQGGPR AP00011 P14662,
WNPFKELERAGQRVRDAVISAAPA 1962 Bactericidin B2 VATVGQAAAIARG
(insect) AP00032 P14663, WNPFKELERAGQRVRDAIISAGPA 1963 Bactericidin
B-3 VATVGQAAAIARG (insect) AP00033 P14664, WNPFKELERAGQRVRDAIISAAPA
1964 Bactericidin B-4 VATVGQAAAIARG (insect) AP00034 P14665,
WNPFKELERAGQRVRDAVISAAA 1965 Bactericidin B-5P VATVGQAAAIARG
(insect) AP00125 P14666, Cecropin RWKIFKKIEKVGQNIRDGIVKAGP 1966
(insect, silk moth) AVAVVGQAATI AP00002 P15450,
YVPLPNVPQPGRRPFPTFPGQGPFN 1967 ABAECIN (insect, PKIKWPQGY honeybee)
AP00505 P15516, human DSHAKRHHGYKRKFHEKHHSHRGY 1968 Histatin 5
(ZZHs; derivatives Dh-5) AP00520 P15516, human
DSHAKRHHGYKRKFHEKHHSHRG 1969 Histatin 3 YRSNYLYDN AP00523 P15516,
human KFHEKHHSHRGY 1970 Histatin 8 AP00226 P17722, Royalisin
VTCDLLSFKGQVNDSACAANCLSL 1971 (insect, honeybee)
GKAGGHCEKVGCICRKTSFKDLW DKRF AP00213 P18252, KWCFRVCYRGICYRKCR 1972
Tachyplesin III (horseshoe crabs, Crustacea) AP00233 P18312,
Sarcotoxin GWIRDFGKRIERVGQHTRDATIQTI 1973 ID (insect, flesh
AVAQQAANVAATLKG AP00207 P19578, Lantibiotic
TAGPAIRASVKQCQKTLKATRLFT 1974 PEP5 (class I VSCKGKNGCK bacteriocin,
bacteria) AP00009 P19660, RFRPPIRRPPIRPPFYPPFRPPIRPPIF 1975
BACTENECIN 5 PPIRPPFRPPLGPFP (bac5, cow cathelicidin) AP00010
P19661, RRIRPRPPRLPRPRPRPLPFPRPGPR 1976 BACTENECIN 7
PIPRPLPFPRPGPRPIPRPLPFPRPGP (bac7, cow RPIPRPL cathelicidin)
AP00200 P21564, LKLKSIVSWAKKVL 1977 Mastoparan B (MP-B, insect,
XXA) AP00005 P21663, Andropin VFIDILDKVENAIHNAAQVGIGFAK 1978
(insect, fly) PFEKLINPK AP00008 P22226, Cyclic RLCRIVVIRVCR 1979
dodecapeptide (cow cathelicidin) AP01205 P23826, Lactocin S
STPVLASVAVSMELLPTASVLYSD 1980 (XXD3, bacteria) VAGCFKYSAKHHC
AP00239 P24335, XPF (the GWASKIGQTLGKIAKVGLKELIQPK 1981 xenopsin
precursor fragment, African clawed frog) AP00235 P25068, Bovine
NPVSCVRNKGICVPIRCPGSMKQIG 1982 tracheal TCVGRAVKCCRKK antimicrobial
peptide (TAP, cow) AP00418 P25230, CAP18 GLRKRLRKFRNKIKEKLKKIGQKIQ
1983 (rabbit cathelicidin, GFVPKLAPRTDY BBL) AP00203 P25403,
Mj-AMP1 QCIGNGGRCNENVGPPYCCSGFCL 1984 (MjAMP1, plant RQPGQGYGYCKNR
defensin) AP00202 P25404, Mj-AMP2 CIGNGGRCNENVGPPYCCSGFCLR 1985
(MjAMP2, plant QPNQGYGVCRNR defensin) AP00138 P28310, Cryptdin-3
LRDLVCYCRKRGCKRRERMNGTC 1986 (Crp3, animal RKGHLMYTLCCR defensin,
alpha, mouse) AP00184 P28794, MBP-1 RSGRGECRRQCLRRHEGQPWETQ 1987
(plant) ECMRRCRRRG AP00050 P29002, Bombinin-
GIGASILSAGKSALKGLAKGLAEHF 1988 like peptide 1 AN (BLP-1, toad)
AP00051 P29003, Bombinin- GIGSAILSAGKSALKGLAKGLAEHF 1989 like
peptide 2 AN (BLP-2, toad) AP00052 P29004, Bombinin-
GIGAAILSAGKSALKGLAKGLAEHF 1990 like peptide 3 (BLP-3, XXA, toad)
AP00053 P29005, Bombinin- GIGAAILSAGKSIIKGLANGLAEHF 1991
like peptide 4 (BLP-4, toad) AP00634 P29430, Pediocin
KYYGNGVTCGKHSCSVDWGKATT 1992 PA-1/AcH CIINNGAMAWATGGHQGNHKC
(PedPA1, class IIA bacteriocin, bacteria) AP00204 P29559, Nisin Z
ITSISLCTPGCKTGALMGCNMKTA 1993 (lantibiotic, class I TCNCSIHVSK
bacteriocin, bacteria) AP00130 P29561, Cecropin
GWLKKLGKRIERIGQHTRDATIQG 1994 C (insect, fly) LGIAQQAANVAATAR
AP00001 P31107, GLWSKIKEVGKEAAKAAAKAAGK 1995 ADENOREGULIN
AALGAVSEAV (Dermaseptin B2, Dermaseptin-B2, DRS-B2, DRS B2, frog)
AP00228 P31529, Sapecin B LTCEIDRSLCLLHCRLKGYLRAYCS 1996 (insect,
flesh fly) QQKVCRCVQ AP00229 P31530, Sapecin C
ATCDLLSGIGVQHSACALHCVFRG 1997 (insect, flesh fly) NRGGYCTGKGICVCRN
AP00218 P32195, Protegrin RGGRLCYCRRRFCICV 1998 2 (PG-2, pig
cathelicidin) AP00219 P32196, Protegrin RGGGLCYCRRRFCVCVGR 1999 3
(PG-3, pig cathelicidin) AP00073 P32412, Brevinin-
FLPLLAGLAANFLPKIFCKITRKC 2000 1E (frog) AP00080 P32414,
GIFSKLGRKKIKNLLISGLKNVGKE 2001 Esculentin-1 (frog)
VGMDVVRTGIDIAGCKIKGEC AP00074 P32423, Brevinin-1
FLPVLAGIAAKVVPALFCKITKKC 2002 (frog) AP00075 P32424, Brevinin-2
GLLDSLKGFAATAGKGVLQSLLST 2003 (frog) ASCKLAKTC AP00175 P34084,
Macaque DSHEERHHGRHGHHKYGRKFHEK 2004 histatin (M-Histatin
HHSHRGYRSNYLYDN 1, primate, monkey) AP00006 P35581, Apidaecin
GNNRPVYIPQPRPPHPRI 2005 IA (insect, honeybee) AP00007 P35581,
Apidaecin GNNRPVYIPQPRPPHPRL 2006 IB (insect, honeybee) AP00414
P36190, SIGSALKKALPVAKKIGKIALPIAK 2007 Ceratotoxin A AALP (insect,
fly) AP00415 P36191, SIGSAFKKALPVAKKIGKAALPIAK 2008 Ceratotoxin B
AALP (insect, fly) AP00172 P36193, Drosocin GKPRPYSPRPTSHPRPIRV
2009 (insect) AP00170 P37362, VDKGSYLPRPTPPRPIYNRN 2010
Pyrrhocoricin (insect) AP00635 P38577, KYYGNGVHCTKSGCSVNWGEAAS 2011
Mesentericin Y105 AGIHRLANGGNGFW (MesY105, class IIA bacteriocin,
bacteria) AP00636 P38579, AISYGNGVYCNKEKCWVNKAENK 2012
Carnobacteriocin QAITGIVIGGWASSLAGMGH BM1 (CnbBM1, PiscV1b, class
IIA bacteriocin, bacteria) AP00209 P39080, Peptide
GVLSNVIGYLKKLGTGALNAVLKQ 2013 PGQ (frog) AP00513 P39084, Ranalexin
FLGGLIKIVPAMICAVTKKC 2014 (frog) AP00071 P40835, Brevinin-
FLPAIFRMAAKVVPTIICSITKKC 2015 1EA (frog) AP00072 P40836, Brevinin-
VIPFVASVAAEMQHVYCAASRKC 2016 1EB (frog) AP00076 P40837, Brevinin-
GILDTLKNLAISAAKGAAQGLVNK 2017 2EA (frog) ASCKLSGQC AP00077 P40838,
Brevinin- GILDTLKNLAKTAGKGALQGLVK 2018 2EB (frog) MASCKLSGQC
AP00078 P40839, Brevinin- GILLDKLKNFAKTAGKGVLQSLLN 2019 2EC (frog)
TASCKLSGQC AP00079 P40840, Brevinin- GILDSLKNLAKNAGQILLNKASCK 2020
2ED (frog) LSGQC AP00081 P40843, GIFSKLAGKKIKNLLISGLKNVGKE 2021
Esculentin-1A VGMDVVRTGIDIAGCKIKGEC (frog) AP00082 P40844,
GIFSKLAGKKLKNLLISGLKNVGK 2022 Esculentin-1B EVGMDVVRTGIDIAGCKIKGEC
(frog) AP00083 P40845, GILSLVKGVAKLAGKGLAKEGGKF 2023 Esculentin-2A
GLELIACKIAKQC (frog) AP00084 P40846, GIFSLVKGAAKLAGKGLAKEGGKF 2024
Esculentin-2B GLELIACKIAKQC (ES2B_RANES, frog) AP00299 P46156,
Chicken GRKSDCFRKSGFCAFLKCPSLTLIS 2025 gallinacin 1 (Gal 1,
GKCSRFYLCCKRIW avian beta- defensin, bird) AP00300 P46157,
Gallinacin GRKSDCFRKNGFCAFLKCPYLTLIS 2026 1 alpha (avian beta-
GKCSRFHLCCKRIW defensin, Bird), AP00298 P46158, Chicken
LFCKGGSCHFGGCPSHLIKVGSCFG 2027 gallinacin 2 (Gal 2, FRSCCKWPWNA
avian beta- defensin, bird) AP00037 P46160, Beta-
VRNHVTCRINRGFCVPIRCPGRTRQ 2028 defensin 2 (cow) IGTCFGPRIKCCRSW
AP00038 P46161, Beta- QGVRNHVTCRINRGFCVPIRCPGR 2029 defensin 3
(cow) TRQIGTCFGPRIKCCRSW AP00039 P46162, Beta-
QRVRNPQSCRWNMGVCIPFLCRV 2030 defensin 4 (cow) GMRQIGTCFGPRVPCCRR
AP00040 P46163, Beta- QVVRNPQSCRWNMGVCIPISCPGN 2031 defensin 5
(cow) MRQIGTCFGPRVPCCRRW AP00041 P46164, Beta-
QGVRNHVTCRIYGGFCVPIRCPGR 2032 defensin 6 (cow) TRQIGTCFGRPVKCCRRW
AP00042 P46165, Beta- QGVRNFVTCRINRGFCVPIRCPGHR 2033 defensin 7
(cow) RQIGTCLGPRIKCCR AP00043 P46166, Beta-
VRNFVTCRINRGFCVPIRCPGHRRQ 2034 defensin 8 (cow) IGTCLGPQIKCCR
AP00044 P46167, Beta- QGVRNFVTCRINRGFCVPIRCPGHR 2035 defensin 9
(cow) RQIGTCLAPQIKCCR AP00045 P46168, Beta-
QGVRSYLSCWGNRGICLLNRCPGR 2036 defensin 10 (cow) MRQIGTCLAPRVKCCR
AP00046 P46169, Beta- GPLSCRRNGGVCIPIRCPGPMRQIG 2037 defensin 11
(cow) TCFGRPVKCCRSW AP00048 P46171, Bovine
SGISGPLSCGRNGGVCIPIRCPVPM 2038 beta-defensin 13 RQIGTCFGRPVKCCRSW
(cow) AP00350 P48821, Enbocin PWNIFKEIERAVARTRDAVISAGPA 2039
(insect, moth) VRTVAAATSVAS AP00173 P49112, GNCP-2
RCICTTRTCRFPYRRLGTCLFQNRV 2040 (Guinea pig YTFCC neutrophil
cationic peptide 2) AP00369 P49930, PMAP-23 RIIDLLWRVRRPQKPKFVTVWVR
2041 (PMAP23, pig cathelicidin) AP00370 P49931, PMAP-36
VGRFRRLRKKTRKRLKKIGKVLK 2042 (PMAP36, pig WIPPIVGSIPLGCG
cathelicidin) AP00371 P49932, PMAP-37 GLLSRLRDFLSDRGRRLGEKIERIG
2043 (PMAP37, pig QKIKDLSEFFQS cathelicidin) AP00220 P49933,
Protegrin RGGRLCYCRGWICFCVGR 2044 4 (PG-4, pig cathelicidin)
AP00221 P49934, Protegrin RGGRLCYCRPRFCVCVGR 2045 5 (PG-5, pig
cathelicidin) AP00346 P50720, Hyphancin RWKIFKKIERVGQNVRDGIIKAGP
2046 IIID (Fall AIQVLGTAKAL webworm, insect) AP00347 P50721,
Hyphancin RWKFFKKIERVGQNVRDGLIKAGP 2047 IIIE (Fall AIQVLGAAKAL
webworm, insect) AP00348 P50722, Hyphancin RWKVFKKIEKVGRNIRDGVIKAGP
2048 IIIF (Fall AIAVVGQAKAL webworm, insect) AP00349 P50723,
Hyphancin RWKVFKKIEKVGRHIRDGVIKAGP 2049 IIIG (Fall AITVVGQATAL
webworm, insect) AP00281 P51473, mCRAMP GLLRKGGEKIGEKLKKIGQKIKNFF
2050 (mouse QKLVPQPEQ cathelicidin; derivatives: CRAMP 18) AP00366
P54228, BMAP-27 GRFKRFRKKFKKLFKKLSPVIPLLH 2051 (BMAP27, cow LG
cathelicidin, ZZHs, derivatives BMAP- 18 and BMAP-15) AP00367
P54229, BMAP-28 GGLRSLGRKILRAWKKYGPIIVPIIR 2052 (BMAP28, cow IG
cathelicidin) AP00450 P54230, Cyclic RICRIIFLRVCR 2053
dodecapeptide (sheep cathelicidin) AP00359 P54684, Lebocin
DLRFLYPRGKLPVPTPPPFNPKPIYI 2054 1/2 (insect, silk DMGNRY moth)
AP00360 P55796, Lebocin 3 DLRFLYPRGKLPVPTLPPFNPKPIYI 2055 (insect,
silk moth) DMGNRY AP00307 P55897, Buforin I AGRGKQGGKVRAKAKTRSSRAGL
2056
(toad) QFPVGRVHRLLRKGNY AP00308 P55897, Buforin II
TRSSRAGLQFPVGRVHRLLRK 2057 (toad) AP00240 P56226, Caerin 1.1
GLLSVLGSVAKHVLPHVVPVIAEHL 2058 (frog, ZZHa) AP00241 P56227, Caerin
1.2 GLLGVLGSVAKHVLPHVVPVIAEHL 2059 (frog) AP00242 P56228, Caerin
1.3 GLLSVLGSVAQHVLPHVVPVIAEHL 2060 (frog) AP00243 P56229, Caerin
1.4 GLLSSLSSVAKHVLPHVVPVIAEHL 2061 (frog) AP00244 P56230, Caerin
1.5 GLLSVLGSVVKHVIPHVVPVIAEHL 2062 (frog) AP00245 P56231, Caerin
1.6 GLFSVLGAVAKHVLPHVVPVIAEK 2063 (frog) AP00246 P56232, Caerin 1.7
GLFKVLGSVAKHLLPHVAPVIAEK 2064 (frog) AP00249 P56233, Caerin 2.1
GLVSSIGRALGGLLADVVKSKGQPA 2065 (frog) AP00250 P56234, Caerin 2.2
GLVSSIGRALGGLLADVVKSKEQPA 2066 (frog) AP00251 P56236, Caerin 2.4
GLVSSIGKALGGLLADVVKTKEQPA 2067 (frog) AP00252 P56236, Caerin 2.5
GLVSSIGRALGGLLADVVKSKEQPA 2068 (frog) AP00253 P56238, Caerin 3.1
GLWQKIKDKASELVSGIVEGVK 2069 (frog) AP00254 P56238, Caerin 3.2
GLWEKIKEKASELVSGIVEGVK 2070 (frog) AP00255 P56240, Caerin 3.3
GLWEKIKEKANELVSGIVEGVK 2071 (frog) AP00256 P56241, Caerin 3.4
GLWEKIREKANELVSGIVEGVK 2072 (frog) AP00257 P56242, Caerin 4.1
GLWQKIKSAAGDLASGIVEGIKS 2073 (frog) AP00258 P56243, Caerin 4.2
GLWQKIKSAAGDLASGIVEGIKS 2074 (frog) AP00259 P56244, Caerin 4.3
GLWQKIKNAAGDLASGIVEGIKS 2075 (frog) AP00434 P56249, Frenatin 3
GLMSVLGHAVGNVLGGLFKS 2076 (frog) AP00272 P56386, Murine
DQYKCLQHGGFCLRSSCPSNTKLQ 2077 beta-defensin 1 GTCKPDKPNCCKS (mBD-1,
mouse) AP00368 P56425, BMAP-34 GLFRRLRDSIRRGQQKILEKARRIG 2078
(BMAP34, cow ERIKDIFRG cathelicidin) AP00273 P56685, Buthinin
SIVPIRCRSNRDCRRFCGFRGGRCT 2079 (Sahara scorpion) YARQCLCGY AP00282
P56872, SIPCGESCVFIPCTVTALLGCSCKSK 2080 Cyclopsychotride VCYKN A
(CPT, plant cyclotides, XXC) AP00094 P56917, Temporin FLPLIGRVLSGIL
2081 A (XXA, frog) AP00096 P56918, Temporin LLPILGNLLNGLL 2082 C
(XXA, frog) AP00097 P56920, Temporin VLPIIGNLLNSLL 2083 E (XXA,
frog) AP00098 P56921, Temporin FLPLIGKVLSGIL 2084 F (XXA, frog)
AP00100 P56923, Temporin LLPNLLKSLL 2085 K (XXA, frog) AP00295
P56928, eNAP-2 EVERKHPLGGSRPGRCPTVPPGTF 2086 (horse)
GHCACLCTGDASEPKGQKCCSN AP00101 P57104, Temporin FVQWFSKFLGRIL 2087
L (XXA, frog) AP00095 P79874, Temporin LLPIVGNLLKSLL 2088 B (XXA,
frog) AP00099 P79875, Temporin FFPVIGRILNGIL 2089 G (XXA, frog)
AP00413 P80032, SLQGGAPNFPQPSQQNGGWQVSP 2090 Coleoptericin
DLGRDDKGNTRGQIEIQNKGKDH (insect) DFNAGWGKVIRGPNKAKPTWHVG GTYRR
AP00396 P80054, PR-39 RRRPRPPYLPRPRPPPFFPPRLPPRIP 2091 (PR39, pig
PGFPPRFPPRFP cathelicidin) AP00182 P80154, Insect
GFGCPLDQMQCHRHCQTITGRSGG 2092 defensin YCSGPLKLTCTCYR AP00444
P80223, GICACRRRFCLNFEQFSGYCRVNG 2093 Corticostatin VI ARYVRCCSRR
(CS-VI) (animal defensin, rabbit) AP00208 P80230, Peptide
RADTQTYQPYNKDWIKEKIYVLLR 2094 3910 (pig) RQAQQAGK AP00157 P80277,
ALWKTMLKKLGTMALHAGKAAL 2095 Dermaseptin-S1 GAAADTISQGTQ
(Dermaseptin S1, DRS S1, DRS-S1, frog) AP00158 P80278,
ALWFTMLKKLGTMALHAGKAAL 2096 Dermaseptin-S2 GAAANTISQGTQ
(Dermaseptin S2, DRS S2, DRS-S2, frog) AP00159 P80279,
ALWKNMLKGIGKLAGKAALGAV 2097 Dermaseptin-S3 KKLVGAES (Dermaseptin
S3, DRS S3, DRS-S3, frog) AP00160 P80280, ALWMTLLKKVLKAAAKALNAVL
2098 Dermaseptin-S4 VGANA (Dermaseptin S4, DRS S4, DRS-S4, frog)
AP00161 P80281, GLWSKIKTAGKSVAKAAAKAAVK 2099 Dermaseptin-S5 AVTNAV
(Dermaseptin S5, DRS S5, DRS-S5, frog) AP00293 P80282,
AMWKDVLKKIGTVALHAGKAAL 2100 Dermaseptin-B1 GAVADTISQ (DRS-B1, DRS
B1, frog) AP00264 P80389, Chicken GRKSDCFRKSGFCAFLKCPSLTLIS 2101
Heterophil Peptide GKCSRFYLCCKRIR 1 (CHP1, bird, animal) AP00265
P80390, Chicken GRKSDCFRKNGFCAFLKCPYLTLIS 2102 Heterophil Peptide
GLCSFHLC 2 (CHP2, bird, animal) AP00266 P80391, Turkey
GKREKCLRRNGFCAFLKCPTLSVIS 2103 Heterophil Peptide GTCSRFQVCC 1
(THP1, turkey) AP00267 P80392, Turkey LFCKRGTCHFGRCPSHLIKVGSCFG
2104 Heterophil Peptide FRSCCKWPWDA 2 (THP2, bird, anaimal) AP00269
P80393, Turkey LSCKRGTCHFGRCPSHLIKGSCSGG 2105 Heterophil Peptide 3
(THP3, bird, animal) AP00085 P80395, Gaegurin-
SLFSLIKAGAKFLGKNLLKQGACY 2106 1 (Gaegurin 1, AACKASKQC frog)
AP00086 P80396, Gaegurin- GIMSIVKDVAKNAAKEAAKGALST 2107 2 (Gaegurin
2, LSCKLAKTC frog) AP00087 P80397, Gaegurin-
GIMSIVKDVAKTAAKEAAKGALST 2108 3 (Gaegurin 3, LSCKLAKTC frog)
AP00089 P80399, Gaegurin- FLGALFKVASKVLPSVFCAITKKC 2109 5 (Gaegurin
5, frog) AP00090 P80400, Gaegurin- FLPLLAGLAANFLPTIICKISYKC 2110 6
(Gaegurin 6, frog) AP00362 P80408, VDKPDYRPRPRPPNM 2111
Metalnikowin I (insect) AP00363 P80409, VDKPDYRPRPWPRPN 2112
Metalnikowin IIA (insect) AP00364 P80410, VDKPDYRPRPWPRNMI 2113
Metalnikowin IIB (insect) AP00365 P80411, VDKPDYRPRPWPRPNM 2114
Metalnikowin III (insect) AP00632 P80569, Piscicolin
KYYGNGVSCNKNGCTVDWSKAIG 2115 126/Piscicocin IIGNNAAANLTTGGAAGWNKG
Via (PiscV1a, Pisc126, class IIA bacteriocin, bacteria) AP01003
P80666, Mutacin FKSWSFCTPGCAKTGSFNSYCC 2116 B-Ny266 (bacteria)
AP00276 P80710, Clavanin VFQFLGKIIHHVGNFVHGFSHVF 2117 A
(urochordates, sea squirts, and sea pork, tunicate) AP00277 P80711,
Clavanin VFQFLGRIIHHVGNFVHGFSHVF 2118 B (Sea squirt, tunicate)
AP00278 P80712, Clavanin VFHLLGKIIHHVGNFVYGFSHVF 2119 C (Sea
squirt, tunicate) AP00279 P80713, Clavanin AFKLLGRIIHHVGNFVYGFSHVF
2120 D (Sea squirt, tunicate) AP00280 P80713, Clavanin
LFKLLGKIIHHVGNFVHGFSHVF 2121 D (Sea squirt, tunicate)
AP00294 P80930, eNAP-1 DVQCGEGHFCHDQTCCRASQGGA 2122 (horse)
CCPYSQGVCCADQRHCCPVGF AP00400 P80952, Skin YPPKPESPGEDASPEEMNKYLTAL
2123 peptide tyrosine- RHYINLVTRQRY tyrosine (skin- PYY, SPYY,
frog) AP00091 P80954, Rugosin A GLLNTFKDWAISIAKGAGKGVLTT 2124
(frog) LSCKLDKSC AP00092 P80955, Rugosin B SLFSLIKAGAKFLGKNLLKQGAQY
2125 (frog) AACKVSKEC AP00093 P80956, Rugosin C
GILDSFKQFAKGVGKDLIKGAAQG 2126 (frog) VLSTMSCKLAKTC AP00392 P81056,
Penaeidin- YRGGYTGPIPRPPPIGRPPLRLVVC 2127 1 (shrimp,
ACYRLSVSDARNCCIKFGSCCHLVK Crustacea) AP00393 P81057, Penaeidin-
YRGGYTGPIPRPPPIGRPPFRPVCN 2128 2a (shrimp,
ACYRLSVSDARNCCIKFGSCCHLVK Crustacea) AP00394 P81058, Penaeidin-
QVYKGGYTRPIPRPPPFVRPLPGGP 2129 3a (shrimp,
IGPYNGCPVSCRGISFSQARSCCSR Crustacea) LGRCCHVGKGYS AP00247 P81251,
Caerin 1.8 GLFKVLGSVAKHLLPHVVPVIAEK 2130 (frog) AP00248 P81252,
Caerin 1.9 GLFGVLGSIAKHVLPHVVPVIAEK 2131 (frog, ZZHa) AP00126
P81417, Cecropin GGLKKLGKKLEGVGKRVFKASEK 2132 A (insect,
ALPVAVGIKALG mosquito) AP00169 P81437, Formaecin GRPNPVNTKPTPYPRL
2133 2 (insect, ants) AP00168 P81438, Formaecin GRPNPVNNKPTPHPRL
2134 1 (insect, ants) AP00296 P81456, Fabatin-1
LLGRCKVKSNRFHGPCLTDTHCST 2135 (plant defensin)
VCRGEGYKGGDCHGLRRRCMCLC AP00297 P81457, Fabatin-2
LLGRCKVKSNRFNGPCLTDTHCST 2136 (plant defensin)
VCRGEGYKGGDCHGLRRRCMCLC AP01215 P81463, European
FVPYNPPRPYQSKPFPSFPGHGPFN 2137 bumblebee abaecin PKIQWPYPLPNPGH
(insect) AP01214 P81464, Apidaecin GNRPVYIPPPRPPHPRL 2138 (insect)
AP00440 P81465, defensin VTCFCRRRGCASRERHIGYCRFGN 2139 HANP-1
(hamster) TIYRLCCRR AP00441 P81466, defensin
CFCKRPVCDSGETQIGYCRLGNTF 2140 HANP-2 (hamster) YRLCCRQ AP00442
P81467, defensin VTCFCRRRGCASRERLIGYCRFGN 2141 HANP-3 (hamster)
TIYGLCCRR AP00439 P81468, defensin VTCFCKRPVCDSGETQIGYCRLGN 2142
HANP-4 (hamster) TFYRLCCRQ AP00328 P81469, Styelin A
GFGKAFHSVSNFAKKHKTA 2143 (Sea squirt, tunicate, XXA) AP00329
P81470, Styelin B GFGPAFHSVSNFAKKHKTA 2144 (Sea squirt, tunicate,
XXA) AP00492 P81474, Misgurin RQRVEELSKFSKKGAAARRRK 2145 (fish)
AP00165 P81485, ALWKNMLKGIGKLAGQAALGAV 2146 Dermaseptin-B3 KTLVGAE
(Dermaseptin B3, DRS-B3, DRS B3, frog) AP00163 P81486,
ALWKDILKNVGKAAGKAVLNTVT 2147 Dermaseptin-B4 DMVNQ (Dermaseptin B4,
DRS-B4, DRS B4, DRS-TR1, IRP, frog) AP00162 P81487,
GLWNKIKEAASKAAGKAALGFVN 2148 Dermaseptin-B5 EMV (Dermaseptin B5,
DRS-B5, DRS B5, frog) AP00164 P81488, ALWKTIIKGAGKMIGSLAKNLLGS 2149
Dermaseptin-B9 QAQPES (Dermaseptin B9, DRS-B9, DRS DRG3, frog)
AP00167 P81565, Phylloxin GWMSKIASGIGTFLSGMQQ 2150 (phylloxin-B1,
PLX-B1, XXA, frog) AP00291 P81568, Defensin
MFFSSKKCKTVSKTFRGPCVRNAN 2151 D5 (So-D5) (plant defensin) AP00290
P81569, Defensin MFFSSKKCKTVSKTFRGPCVRNA 2152 D4 (So-D4) (plant
defensin) AP00289 P81570, Defensin GIFSSRKCKTVSKTFRGICTRNANC 2153
D3 (So-D3) (plant defensin) AP00288 P81572, Defensin
TCESPSHKFKGPCATNRNCES 2154 D1 (So-D1) (plant defensin) AP00292
P81573, Defensin GIFSSRKCKTPSKTFKGYCTRDSNC 2155 D7 (So-D7) (plant
DTSCRYEGYPAGD defensin) AP00270 P81591, Pn-AMP
QQCGRQASGRLCGNRLCCSQWGY 2156 (PnAMP, plant CGSTASYCGAGCQSQCRS
defensin) AP00412 P81592, SLQPGAPNVNNKDQPWQVSPHISR 2157 Acaloleptin
A1 DDSGNTRTDINVQRHGENNDFEAG (insect) WSKVVRGPNKAKPTWHIGGTHRW
AP00433 P81605, human SSLLEKGLDGAKKAVGGLGKLGK 2158 Dermcidin (DCD-
DAVEDLESVGKGAVHDVKDVLDSV 1) AP00332 P81612, Mytilin A
GCASRCKAKCAGRRCKGWASASF 2159 (Blue mussel) RGRCYCKCFRC AP00333
P81613, Mytilin B SCASRCKGHCRARRCGYYVSVLY 2160 (Blue mussel)
RGRCYCKCLRC AP00334 P81613, FFHHIFRGIVHVGKTIHKLVTG 2161 Moronecidin
(fish) AP00351 P81835, Citropin GLFDVIKKVASVIGGL 2162 1.1
(amphibian, frog) AP00352 P81840, Citropin GLFDIIKKVASVVGGL 2163
1.2 (amphibian, frog) AP00353 P81846, Citropin GLFDIIKKVASVIGGL
2164 1.3 (amphibian, frog) AP00338 P81903, Histone
PDPAKTAPKKGSKKAVTKA 2165 H2B-1(HLP-1) (fish) AP00271 P82018, ChBac5
RFRPPIRRPPIRPPFNPPFRPPVRPPF 2166 (Goat cathelicidin)
RPPFRPPFRPPIGPFP AP00316 P82027, Uperin 2.1 GIVDFAKKVVGGIRNALGI
2167 (amphibian, toad) AP00317 P82028, Uperin 2.2
GFVDLAKKVVGGIRNALGI 2168 (amphibian, toad) AP00318 P82029, Uperin
2.3 GFFDLAKKVVGGIRNALGI 2169 (amphibian, toad) AP00319 P82030,
Uperin 2.4 GILDFAKTVVGGIRNALGI 2170 (amphibian, toad) AP00320
P82031, Uperin 2.5 GIVDFAKGVLGKIKNVLGI 2171 (amphibian, toad)
AP00323 P82032, Uperin 3.1 GVLDAFRKIATVVKNVV 2172 (amphibian, toad)
AP00326 P82035, Uperin 4.1 GVGSFIHKVVSAIKNVA 2173 (amphibian, toad)
AP00321 P82039, Uperin 2.7 GIIDIAKKLVGGIRNVLGI 2174 (amphibian,
toad) AP00322 P82040, Uperin 2.8 GILDVAKTLVGKLRNVLGI 2175
(amphibian, toad) AP00324 P82042, Uperin 3.5 GVGDLIRKAVSVIKNIV 2176
(amphibian, toad) AP00325 P82042, Uperin 3.6 GVIDAAKKVVNVLKNLP 2177
(amphibian, toad) AP00327 P82050, Uperin 7.1 GWFDVVKHIASAV 2178
(amphibian, frog) AP00260 P82066, Maculatin GLFVGVLAKVAAHVVPAIAEHF
2179 1.1 (XXA, frog, ZZHa) AP00261 P82067, Maculatin
GLFVGLAKVAAHNNPAIAEHFQA 2180 1.2 (XXA, frog) AP00262 P82068,
Maculatin GFVDFLKKVAGTIANVVT 2181 2.1 (frog) AP00263 P82069,
Maculatin GLLQTIKEKLESLESLAKGIVSGIQA 2182 3.1 (frog) AP00345
P82104, Caerin GLLSVLGSVAKHVLPHVVPVIAEKL 2183 1.10 (frog) AP00456
P82232, Brevinin- VNPIILGVLPKFVCLITKKC 2184 1T (frog) AP00459
P82233, Brevinin- FITLLLRKFICSITKKC 2185 1TA (frog) AP00457 P82234,
Brevinin- GLWETIKNFGKKFTLNILHKLKCKI 2186 2TC (frog) GGGC AP00458
P82235, Brevinin- GLWETIKNFGKKFTLNILHNLKCKI 2187 2TD (frog) GGGC
AP00397 P82238, SGFVLKGYTKTSQ 2188 Salmocidin 2A (fish, trout)
AP00398 P82239, AGFVLKGYTKTSQ 2189 Salmocidin 2B (fish, trout)
AP00055 P82282, Bombinin IIGPVLGMVGSALGGLLKKI 2190 H1 (frog)
AP00056 P82284, Bombinin LIGPVLGLVGSALGGLLKKI 2191 H4 (frog, XXA,
XXD) AP00057 P82285, Bombinin IIGPVLGLVGSALGGLLKKI 2192
H5 (frog, XXD) AP00419 P82286, Bombinin- GIGASILSAGKSALKGFAKGLAEHF
2193 like peptides 2 AN (amphibian, toad) AP00137 P82293,
Cryptdin-1 LRDLVCYCRTRGCKRRERMNGTC 2194 (Crp1, animal RKGHLMYTLCCR
defensin, alpha, mouse) AP00443 P82317, defensin
ACYCRIPACLAGERRYGTCFYMGR 2195 RMAD-2 (monkey) VWAFCC AP00012
P82386, Aurein 1.1 GLFDIIKKIAESI 2196 (amphibian, frog) AP00014
P82388, Aurein 2.1 GLLDIVKKVVGAFGSL 2197 (amphibian, frog) AP00015
P82389, Aurein 2.2 GLFDIVKKVVGALGSL 2198 (amphibian, frog) AP00016
P82390, Aurein 2.3 GLFDIVKKVVGAIGSL 2199 (XXA, amphibian, frog)
AP00017 P82391, Aurein 2.4 GLFDIVKKVVGTIAGL 2200 (XXA, amphibian,
frog) AP00018 P82392, Aurein 2.5 GLFDIVKKVVGAFGSL 2201 (XXA,
amphibian, frog) AP00019 P82393, Aurein 2.6 GLFDIAKKVIGVIGSL 2202
(XXA, amphibian, frog) AP00020 P82394, Aurein 3.1 GLFDIVKKIAGHIAGSI
2203 (XXA, amphibian, frog) AP00021 P82395, Aurein 3.2
GLFDIVKKIAGHIASSI 2204 (XXA, amphibian, frog) AP00022 P82396,
Aurein 3.3 GLFDIVKKIAGHIVSSI 2205 (XXA, amphibian, frog) AP00376
P82414, Ponericin GWKDWAKKAGGWLKKKGPGMA 2206 G1 (ants) KAALKAAMQ
AP00377 P82415, Ponericin GWKDWLKKGKEWLKAKGPGIVK 2207 G2 (ants)
AALQAATQ AP00378 P82416, Ponericin GWKDWLNKGKEWLKKKGPGIMK 2208 G3
(ants) AALKAATQ AP00379 P82417, Ponericin DFKDWMKTAGEWLKKKGPGILKA
2209 G4 (ants) AMAAAT AP00380 P82418, Ponericin
GLKDWVKIAGGWLKKKGPGILKA 2210 G5 (ants) AMAAATQ AP00381 P82419,
Ponericin GLVDVLGKVGGLIKKLLP 2211 G6 (ants) AP00382 P82420,
Ponericin GLVDVLGKVGGLIKKLLPG 2212 G7 (ants) AP00383 P82421,
Ponericin LLKELWTKMKGAGKAVLGKIKGLL 2213 L1 (ants) AP00384 P82422,
Ponericin LLKELWTKIKGAGKAVLGKIKGLL 2214 L2 (ants) AP00386 P82423,
Ponericin WLGSALKIGAKLLPSVVGLFKKKKQ 2215 W1 (ants) AP00387 P82424,
Ponericin WLGSALKIGAKLLPSVVGLFQKKKK 2216 W2 (ants) AP00388 P82425,
Ponericin GIWGTLAKIGIKAVPRVISMLKKK 2217 W3 (ants) KQ AP00389
P82426, Ponericin GIWGTALKWGVKLLPKLVGMAQT 2218 W4 (ants) KKQ
AP00390 P82427, Ponericin FWGALIKGAAKLIPSVVGLFKKKQ 2219 W5 (ants)
AP00391 P82428, Ponericin FIGTALGIASAIPAIVKLFK 2220 W6 (ants)
AP00303 P82651, Tigerinin- FCTMIPIPRCY 2221 1 (frog) AP00304
P82652, Tigerinin- RVCFAIPLPICH 2222 2 (frog) AP00305 P82653,
Tigerinin- RVCYAIPLPICY 2223 3 (frog) AP00301 P82656, Hadrurin
GILDTIKSIASKVWNSKTVQDLKR 2224 (scorpion) KGINWVANKLGVSPQAA AP00113
P82740, GLLSGLKKVGKHVAKNVAVSLMD 2225 RANATUERIN 1T SLKCKISGDC
(frog) AP00114 P82741, SMLSVLKNLGKVGLGFVACKINK 2226 RANATUERIN 1 QC
(Ranatuerin-1, frog) AP00115 P82742, GLFLDTLKGAAKDVAGKLEGLKC 2227
RANATUERIN 2 KITGCKLP (Ranatuerin-2, frog) AP00116 P82780,
GFLDIINKLGKTFAGHMLDKIKCTI 2228 RANATUERIN 3 GTCPPSP (Ranatuerin-3,
frog) AP00117 P82819, FLPFIARLAAKVFPSIICSVTKKC 2229 RANATUERIN 4
(Ranatuerin-4, frog) AP00405 P82821, FISAIASMLGKFL 2230 RANATUERIN
6 (frog) AP00406 P82822, FLSAIASMLGKFL 2231 RANATUERIN 7 (frog)
AP00407 P82823, FISAIASFLGKFL 2232 RANATUERIN 8 (frog) AP00408
P82824, FLFPLITSFLSKVL 2233 RANATUERIN 9 (frog) AP00461 P82825,
Brevinin- FLPMLAGLAASMVPKLVCLITKKC 2234 1LA (frog) AP00462 P82826,
Brevinin- FLPMLAGLAASMVPKFVCLITKKC 2235 1LB (frog) AP00118 P82828,
GILDSFKGVAKGVAKDLAGKLLD 2236 RANATUERIN KLKCKITGC 2La (Ranatuerin-
2La, frog) AP00119 P82829, GILSSIKGVAKGVAKNVAAQLLDT 2237 RANATUERIN
LKCKITGC 2Lb (Ranatuerin- 2Lb, frog) AP00109 P82830, Temporin-
VLPLISMALGKLL 2238 1La (Temporin 1La, frog) AP00110 P82831,
Temporin- NFLGTLINLAKKIM 2239 1Lb (Temporin 1Lb, frog) AP00111
P82832, Temporin- FLPILINLIHKGLL 2240 1Lc (Temporin 1Lc, frog)
AP00463 P82833, Brevinin- FLPFIAGMAAKFLPKIFCAISKKC 2241 1BA (frog)
AP00464 P82834, Brevinin- FLPAIAGMAAKFLPKIFCAISKKC 2242 1BB (frog)
AP00465 P82835, Brevinin- FLPFIAGVAAKFLPKIFCAISKKC 2243 1BC (frog)
AP00466 P82836, Brevinin- FLPAIAGVAAKFLPKIFCAISKKC 2244 1BD (frog)
AP00467 P82837, Brevinin- FLPAIVGAAAKFLPKIFCVISKKC 2245 1BE (frog)
AP00468 P82838, Brevinin- FLPFIAGMAANFLPKIFCAISKKC 2246 1BF (frog)
AP00120 P82840, GLLDTIKGVAKTVAASMLDKLKC 2247 RANATUERIN 2B KISGC
(Ranatuerin-2B, frog) AP00469 P82841, Brevinin-
FLPIIAGVAAKVFPKIFCAISKKC 2248 1PA (frog) AP00460 P82842, Brevinin-
FLPIIAGIAAKVFPKIFCAISKKC 2249 1PB (frog) AP00470 P82843, Brevinin-
FLPIIASVAAKVFSKIFCAISKKC 2250 1PC (frog) AP00471 P82844, Brevinin-
FLPIIASVAANVFSKIFCAISKKC 2251 1PD (frog) AP00472 P82845, Brevinin-
FLPIIASVAAKVFPKIFCAISKKC 2252 1PE (frog) AP00121 P82847,
GLMDTVKNVAKNLAGHMLDKLK 2253 RANATUERIN 2P CKITGC (Ranatuerin-2P,
frog) AP00112 P82848, Temporin- FLPIVGKLLSGLL 2254 1P (Temporin 1P,
frog) AP00452 P82871, Brevinin- FLPVVAGLAAKVLPSIICAVTKKC 2255 1SY
(frog) AP00122 P82875, SMLSVLKNLGKVGLGLVACKINK 2256 Ranatuerin-1C
QC (Ranatuerin 1C, frog) AP00514 P82876, Ranalexin-
FLGGLMKAFPALICAVTKKC 2257 1Ca (frog) AP00515 P82877, Ranalexin-
FLGGLMKAFPAIICAVTKKC 2258 1Cb (frog) AP00124 P82878,
GLFLDTLKGAAKDVAGKLLEGLK 2259 Ranatuerin-2Ca CKIAGCKP (Ranatuerin
2Ca, frog) AP00123 P82879, GLFLDTLKGLAGKLLQGLKCIKAG 2260
Ranatuerin-2Cb CKP (Ranatuerin 2Cb, frog) AP00104 P82880, Temporin-
FLPFLAKILTGVL 2261 1Ca (Temporin 1Ca, frog)
AP00105 P82881, Temporin- FLPLFASLIGKLL 2262 1Cb (Temporin 1Cb,
frog) AP00106 P82882, Temporin- FLPFLASLLTKVL 2263 1Cc (Temporin
1Cc, frog) AP00107 P82883, Temporin- FLPFLASLLSKVL 2264 1Cd
(Temporin 1Cd, frog) AP00108 P82884, Temporin- FLPFLATLLSKVL 2265
1Ce (Temporin 1Ce, frog) AP00453 P82904, Brevinin-
FLPAIVGAAGQFLPKIFCAISKKC 2266 1SA (frog) AP00454 P82905, Brevinin-
FLPAIVGAAGKFLPKIFCAISKKC 2267 1SB (frog) AP00455 P82906, Brevinin-
FFPIVAGVAGQVLKKIYCTISKKC 2268 1SC (frog) AP00996 P82907, Lichenin
ISLEICAIFHDN 2269 (bacteria) AP00302 P82951, Hepcidin
GCRFCCNCCPNMSGCGVCCRF 2270 (fish) AP00058 P83080, Maximin 1
GIGTKILGGVKTALKGALKELAST 2271 (toad) YAN AP00059 P83081, Maximin 2
GIGTKILGGVKTALKGALKELAST 2272 (toad) YVN AP00060 P83082, Maximin 3
GIGGKILSGLKTALKGAAKELAST 2273 (toad, ZZHa) YLH AP00061 P83083,
Maximin 4 GIGGVLLSAGKAALKGLAKVLAE 2274 (toad) KYAN AP00062 P83084,
Maximin 5 SIGAKILGGVKTFFKGALKELASTY 2275 (toad) LQ AP00063 P83085,
Maximin 6 ILGPVISTIGGVLGGLLKNL 2276 (toad) AP00064 P83086, Maximin
7 ILGPVLGLVGNALGGLIKNE 2277 (toad) AP00065 P83087, Maximin 8
ILGPVLSLVGNALGGLLKNE 2278 (toad) AP00355 P83171,
ANTAFVSSAHNTQKIPAGAPFNRN 2279 Ginkbilobin LRAMLADLRQNAAFAG (Chinese
plant) AP00475 P83188, Pseudin 1 GLNTLKKVFQGLHEAIKLINNHVQ 2280
(frog) AP00476 P83189, Pseudin 2 GLNALKKVFQGIHEAIKLINNHVQ 2281
(frog) AP00477 P83190, Pseudin 3 GINTLKKVIQGLHEVIKLVSNHE 2282
(frog) AP00478 P83191, Pseudin 4 GINTLKKVIQGLHEVIKLVSNHA 2283
(frog) AP00410 P83287, SKGKKANKDVELARG 2284 Oncorhyncin III (fish)
AP00357 P83305, Japonicin- FFPIGVFCKIFKTC 2285 1 (amphibian, frog)
AP00358 P83306, Japonicin- FGLPMLSILPKALCILLKRKC 2286 2 (amphibian,
frog) AP00385 P83312, FKLGSFLKKAWKSKLAKKLRAKG 2287 Parabutoporin
KEMLKDYAKGLLEGGSEEVPGQ (scorpion) AP00374 P83313,
GKVWDWIKSTAKKLWNSEPVKEL 2288 Opistoporin 1 KNTALNAAKNLVAEKIGATPS
(scorpion) AP00375 P83314, GKVWDWIKSTAKKLWNSEPVKEL 2289 Opistoporin
2 KNTALNAAKNFVAEKIGATPS (scorpion) AP00336 P83327, Histone
AERVGAGAPVYL 2290 H2A (fish) AP00335 P83338, Histone PKRKSATKGDEPA
2291 H6-like protein (fish) AP00411 P83374, KAVAAKKSPKKAKKPAT 2292
Oncorhyncin II (fish) AP00999 P83375, Serracin-P DYHHGVRVL 2293 43
kDa subunit (bacteria) AP00284 P83376, SHQDCYEALHKCMASHSKPFSCS 2294
Dolabellanin B2 MKFHMCLQQQ (sea hare) AP00998 P83378, Serracin-P
ALPKKLKYLNLFNDGFNYMGVV 2295 23 kDa subunit (bacteriocin, bacteria)
AP00129 P83403, Cecropin GWLKKIGKKIERVGQNTRDATVK 2296 (insect,
moth) GLEVAQQAANVAATVR AP00127 P83413, Cecropin
RWKVFKKIEKVGRNIRDGVIKAAP 2297 A (insect, moth) AIEVLGQAKAL AP00372
P83416, Virescein GKIPIGAIKKAGKAIGKGLRAVNIA 2298 (insect)
STAHDVYTFFKPKKRH AP00356 P83427, Heliocin QRFIHPTYRPPPQPRRPVIMRA
2299 (insect) AP00409 P83428, Locustin ATTGCSCPQCIIFDPICASSYKNGRR
2300 (insect) GFSSGCHMRCYNRCHGTDYFQISK GSKCI AP00339 P83545,
FFGWLIKGAIHAGKAIHGLIHRRRH 2301 Chrysophsin-1 (Red sea bream, madai)
AP00340 P83546, FFGWLIRGAIHAGKAIHGLIHRRRH 2302 Chrysophsin-2 (Red
sea bream, madai) AP00341 P83547, FIGLLISAGKAIHDLIRRRH 2303
Chrysophsin-3 (Red sea bream, madai) AP01004 P84763, Thuricin-S
DWTAWSALVAAACSVELL 2304 (bacteria) AP00553 P84868, Sesquin
KTCENLADTY 2305 (plant, ZZHp) AP00132 Q06589, Cecropin
GWLKKIGKKIERVGQHTRDATIQTI 2306 1 (insect, fly) AVAQQAANVAATAR
AP00135 Q06590, Cecropin GWLKKIGKKIERVGQHTRDATIQTI 2307 2 (insect
fly) GVAQQAANVAATLK AP00416 Q17313, SLGGVISGAKKVAKVAIPIGKAVLP 2308
Ceratotoxin C VVAKLVG (insect, fly) AP00171 Q24395,
HRHQGPIFDTRPSPFNPNQPRPGPIY 2309 Metchnikowin (insect) AP00354
Q27023, Tenecin 1 VTCDILSVEAKGVKLNDAACAAH 2310 (insect)
CLFRGRSGGYCNGKRVCVCR AP00401 Q28880, Lingual
GFTQGVRNSQSCRRNKGICVPIRCP 2311 antimicrobial GSMRQIGTCLGAQVKCCRRK
peptide (LAP, beta defensin, cow) AP00224 Q62713, RatNP-3
CSCRTSSCRFGERLSGACRLNGRIY 2312 (rat) RLCC AP00225 Q62714, RatNP-4
ACYCRIGACVSGERLTGACGLNGR 2313 (rat) IYRLCCR AP00223 Q62715, RatNP-2
VTCYCRSTRCGFRERLSGACGYRG 2314 (rat) RIYRLCCR AP00222 Q62716,
RatNP-1 VTCYCRRTRCGFRERLSGACGYRG 2315 (rat) RIYRLCCR AP00174
Q64365, GNCP-1 RRCICTTRTCRFPYRRLGTCIFQNR 2316 (Guinea pig VYTFCC
neutrophil cationic peptide 1) AP00311 Q90W78, Galensin
CYSAAKYPGFQEFINRKYKSSRF 2317 (frog) AP00395 Q95NT0,
HSSGYTRPLPKPSRPIFIRPIGCDVC 2318 Penaeidin-4a YGIPSSTARLCCFRYGDCCHR
(shrimp, Crustacea) AP00423 Q962B0, QGYKGPYTRPILRPYVRPVVSYNA 2319
Penaeidin-3n CTLSCRGITTTQARSCSTRLGRCCH (shrimp, Crustacea) VAKGYS
AP00422 Q962B1, QGCKGPYTRPILRPYVRPVVSYNA 2320 Penaeidin-3m
CTLSCRGITTTQARSCCTRLGRCCH (shrimp, Crustacea) VAKGYS AP00421
Q963C3, YSSGYTRPLPKPSRPIFIRPIGCDVC 2321 Penaeidin-4C
YGIPSSTARLCCFRYGDCCHR (shrimp, Crustacea) AP00210 Q99134, PGLa
GMASKAGAIAGKIAKVALKAL 2322 (African clawed frog, XXA) AP00054
Q9DET7, GIGGALLSAGKSALKGLAKGLAEH 2323 Bombinin-like FAN peptide 7
(BLP-7, toad) AP00315 Q9PT75, SLGSFLKGVGTTLASVGKVVSDQF 2324
Dermatoxin (Two- GKLLQAGQ colored leaf frog) AP00133 Q9Y0Y0,
Cecropin GGLKKLGKKLEGVGKRVFKASEK 2325 B (insect, ALPVLTGYKAIG
mosquito) AP00004 Ref, Ct-AMP1 NLCERASLTWTGNCGNTGHCDTQ 2326
(CtAMP1, C. CRNWESAKHGACHKRGNWKCFC ternatea- YFDC antimicrobial
peptide 1, plant defensin) AP00027 Ref, hexapeptide RRWQWR 2327
(synthetic) AP00529 Ref, Lantibiotic WKSESVCTPGCVTGVLQTCFLQTI 2328
Ericin S (bacteria) TCNCHISK AP00306 Ref, Tigerinin-4 RVCYAIPLPIC
2329 (frog) AP00309 Ref, Human KS-27 KSKEKIGKEFKRIVQRIKDFLRNLV 2330
(KS27 from LL-37) PR AP00344 Ref, Apidaecin II GNNRPIYIPQPRPPHPRL
2331 (honeybee, insect)
AP00424 Ref, XT1 (frog) GFLGPLLKLAAKGVAKVIPHLIPSR 2332 QQ AP00425
Ref, XT 2 (frog) GCWSTVLGGLKKFAKGGLEAIVNPK 2333 AP00426 Ref, XT 4
(frog) GVFLDALKKFAKGGMNAVLNPK 2334 AP00427 Ref, XT 7 (frog)
GLLGPLLKIAAKVGSNLL 2335 AP00431 Ref, human LLP 1
RVIEVVQGACRAIRHIPRRIRQGLE 2336 RIL AP00432 Ref, human LLP
RIAGYGLRGLAVIIRICIRGLNLIFEI 2337 IR AP00447 Ref, Anoplin GLLKRIKTLL
2338 (insect) AP00474 Ref, Piscidin 3 FIHHIFRGIVHAGRSIGRFLTG 2339
(fish) AP00481 Ref, Kaliocin-1 FFSASCVPGADKGQFPNLCRLCAG 2340
(synthetic) TGENKCA AP00482 Ref, Thionin KSCCRNTWARNCYNVCRLPGTISR
2341 mutation EICAKKCRCKIISGTTCPSDYPK (synthetic) AP00484 Ref,
Stomoxyn RGFRKHFNKLVKKVKHTISETAHV 2342 (insect, fly)
AKDTAVIAGSGAAVVAAT AP00486 Ref, Cupiennin 1b
GFGSLFKFLAKKVAKTVAKQAAK 2343 (spider) QGAKYIANKQME AP00487 Ref,
Cupiennin 1c GFGSLFKFLAKKVAKTVAKQAAK 2344 (spider) QGAKYIANKQTE
AP00488 Ref, Cupiennin 1D GFGSLFKFLAKKVAKTVAKQAAK 2345 (spider)
QGAKYVANKHME AP00489 Ref, Hipposin SGRGKTGGKARAKAKTRSSRAGL 2346
(fish) QFPVGRVHRLLRKGNYAHRVGAG APVYL AP00923 Ref,
AISYGNGVYCNKEKCWVNKAENK 2347 Carnobacteriocin QAITGIVIGGWASSLAGMGH
B1 (XXO, class IIa bacteriocin, bacteria) AP00496 Ref, HP 2-20
AKKVFKRLEKLFSKIQNDK 2348 (synthetic) AP00497 Ref, Maximin H5
ILGPVLGLVSDTLDDVLGIL 2349 (toad) AP00498 Ref, rCRAMP (rat
GLVRKGGEKFGEKLRKIGQKIKEF 2350 cathelicidin) FQKLALEIEQ AP00500 Ref,
S9-P18 KWKLFKKISKFLHLAKKF 2351 (synthetic) AP00501 Ref, L9-P18
KWKLFKKILKFLHLAKKF 2352 (synthetic) AP00502 Ref, Clavaspirin
FLRFIGSVIHGIGHLVHHIGVAL 2353 (sea squirt, tunicate) AP00503 Ref,
human P- AKRHHGYKRKFH 2354 113D AP00504 Ref, human MUC7
LAHQKPFIRKSYKCLHKRCR 2355 20-Mer AP00507 Ref, Nigrocin 2
GLLSKVLGVGKKVLCGVSGLC 2356 (frog) AP00508 Ref, Nigrocin 1
GLLDSIKGMAISAGKGALQNLLKV 2357 (frog) ASCKLDKTC AP00509 Ref, human
VAIALKAAHYHTHKE 2358 Calcitermin AP00510 Ref, Dicynthaurin
ILQKAVLDCLKAAGSSLSKAAITAI 2359 (sea peach) YNKIT AP00511 Ref,
KIGAKI KIGAKIKIGAKIKIGAKI 2360 (synthetic) AP00516 Ref, Lycotoxin I
IWLTALKFLGKHAAKHLAKQQLS 2361 (spider) KL AP00517 Ref, Lycotoxin II
KIKWFKTMKSIAKFIAKEQMKKHL 2362 (spider) GGE AP00518 Ref, Ib-AMP3
QYRHRCCAWGPGRKYCKRWC 2363 (plant defensin, balsam) AP00519 Ref,
Ib-AMP4 EWGRRCCGWGPGRRYCRRWC 2364 (plant defensin, balsam) AP00521
Ref, Dhvar4 KRLFKKLLFSLRKY 2365 (synthetic) AP00522 Ref, Dhvar5
LLLFLLKKRKKRKY 2366 (synthetic) AP00525 Ref, Maximin H2
ILGPVLSMVGSALGGLIKKI 2367 (toad) AP00526 Ref, Maximin H3
ILGPVLGLVGNALGGLIKKI 2368 (toad) AP00527 Ref, Maximin H4
ILGPVISKIGGVLGGLLKNL 2369 (toad) AP00528 Ref, Anionic DDDDDD 2370
peptide SAAP (sheep) AP00530 Ref, Lantibiotic
VLSKSLCTPGCITGPLQTCYLCFPT 2371 Ericin A (bacteria) FAKC AP00531
Ref, Kenojeinin I GKQYFPKVGGRLSGKAPLAAKTH 2372 (sea skate) RRLKP
AP00532 Ref, Lunatusin KTCENLADTFRGPCFATSNC 2373 (plant, ZZHp)
AP00533 Ref, Fallaxin (frog) GVVDILKGAAKDIAGHLASKVMN 2374 KL
AP00534 Ref, Tu-AMP 2 KSCCRNTTARNCYNVCRIPG 2375 (TuAMP2, thionin-
like antimicrobial peptides, plant defensin, tulip) AP00535 Ref,
Pilosulin 1 GLGSVFGRLARILGRVIPKVAKKL 2376 (Myr b I)
GPKVAKVLPKVMKEAIPMAVEMA (Australian ants) KSQEEQQPQ AP00536 Ref,
Luxuriosin SVRTQDNAVNRQIFGSNGPYRDFQ 2377 (insect)
LSDCYLPLETNPYCNEWQFAYHW NNALMDCERAIYHGCNRTRNNFIT LTACKNQAGPICNRRRH
AP00537 Ref, SAMP H1 AEVAPAPAAAAPAKAPKKKAAAK 2378 (fish, Atlantic
PKKAGPS salmon) AP00538 Ref, Halocidin WLNALLHHGLNCAKGVLA 2379
(dimer Hal18 + Hal15) (tunicate) AP00539 Ref, AOD
GFGCPWNRYQCHSHCRSIGRLGGY 2380 (American oyster CAGSLRLTCTCYRS
defensin, animal defensin) AP00540 Ref, Pentadactylin
GLLDTLKGAAKNVVGSLASKVME 2381 (frog) KL AP00541 Ref, Polybia-MPI
IDWKKLLDAAKQIL 2382 (insect, social wasp) AP00542 Ref, Polybia-CP
ILGTILGLLKSL 2383 (insect, social wasp) AP00543 Ref, Ocellatin-1
GVVDILKGAGKDLLAHLVGKISEKV 2384 (XXA, frog) AP00544 Ref, Ocellatin-2
GVLDIFKDAAKQILAHAAEKQI 2385 (XXA, frog) AP00545 Ref, Ocellatin-3
GVLDILKNAAKNILAHAAEQI 2386 (frog) AP00548 Ref, CMAP 27
RFGRFLRKIRRFRPKVTITIQGSARFG 2387 (chicken myeloid antimicrobial
peptide 27, bird cathelicidin, chicken cathelicidin) AP00550 Ref,
Tu-AMP-1 KSCCRNTVARNCYNVCRIPGTPRP 2388 (TuAMP1, thionin-
VCAATCDCKLITGTKCPPGYEK like antimicrobial peptides, plant defensin,
tulip) AP00551 Ref, Combi-2 FRWWHR 2389 (synthetic) AP00552 Ref,
Maximin 9 GIGRKFLGGVKTTFRCGVKDFASK 2390 (frog) HLY AP00554 Ref, Sl
moricin GKIPVKAIKKAGAAIGKGLRAINIA 2391 (insect) STAHDVYSFFKPKHKKK
AP00555 Ref, Parasin I KGRGKQGGKVRAKAKTRSS 2392 (catfish) AP00556
Ref, Kassinatuerin- GFMKYIGPLIPHAVKAISDLI 2393 1 (frog) AP00557
Ref, Fowlicidin-1 RVKRVWPLVIRTVIAGYNLYRAIK 2394 (chCATH-1, bird KK
cathelicidin, chicken cathelicidin) AP00559 Ref, Eryngin
ATRVVYCNRRSGSVVGGDDTVYY 2395 (mushroom, fungi) EG AP00560 Ref,
Dendrocin TTLTLHNLCPYPVWWLVTPNNGG 2396 (plant, bamboo) FPIIDNTPVVLG
AP00561 Ref, Coconut EQCREEEDDR 2397 antifungal peptide (plant)
AP00562 Ref, Pandinin 1 GKVWDWIKSAAKKIWSSEPVSQL 2398 (African
scorpion) KGQVLNAAKNYVAEKIGATPT AP00563 Ref, White cloud
KTCENLADTFRGPCFATSNCDDHC 2399 bean defensin KNKEHLLSGRCRDDFRCWCTRNC
(plant defensin) AP00564 Ref, Dybowskin-1 FLIGMTHGLICLISRKC 2400
(frog) AP00565 Ref, Dybowskin-2 FLIGMTQGLICLITRKC 2401 (frog)
AP00566 Ref, Dybowskin-3 GLFDVVKGVLKGVGKNVAGSLLE 2402 (frog)
QLKCKLSGGC AP00567 Ref, Dybowskin-4 VWPLGLVICKALKIC 2403 (frog)
AP00568 Ref, Dybowskin-5 GLFSVVTGVLKAVGKNVAKNVGG 2404 (frog)
SLLEQLKCKKISGGC AP00569 Ref, Dybowskin-6 FLPLLLAGLPLKLCFLFKKC
2405
(frog) AP00570 Ref, Pleurain-A1 SIITMTKEAKLPQLWKQIACRLYNTC 2406
(frog) AP00571 Ref, Pleurain-A2 SIITMTKEAKLPQSWKQIACRLYNTC 2407
(frog) AP00574 Ref, Esculentin- GLFSKFAGKGIKNLIFKGVKHIGKE 2408 IGRa
(frog) VGMDVIRTGIDVAGCKIKGEC AP00575 Ref, Brevinin-
GLLDTFKNLALNAAKSAGVSVLNS 2409 2GRa (frog) LSCKLSKTC AP00576 Ref,
Brevinin- GVLGTVKNLLIGAGKSAAQSVLKT 2410 2GRb (frog) LSCKLSNDC
AP00577 Ref, Brevinin- GLFTLIKGAAKLIGKTVAKEAGKT 2411 2GRc (frog)
GLELMACKITNQC AP00578 Ref, Brevinin- FLPLLAGLAANFLPKIFCKITKKC 2412
1GRa (frog) AP00579 Ref, Nigrocin- GLLSGILGAGKHIVCGLSGLC 2413 2GRa
(frog) AP00580 Ref, Nigrocin- GLFGKILGVGKKVLCGLSGMC 2414 2GRb
(frog) AP00581 Ref, Nigrocin- GLLSGILGAGKNIVCGLSGLC 2415 2GRc
(frog) AP00582 Ref, Brevinin- GFSSLFKAGAKYLLKSVGKAGAQ 2416 2GHa
(frog) QLACKAANNCA AP00583 Ref, Brevinin- GVITDALKGAAKTVAAELLRKAH
2417 2GHb (frog) CKLTNSC AP00584 Ref, Guentherin
VIDDLKKVAKKVRRELLCKKHHK 2418 (frog) KLN AP00585 Ref, Brevinin-
SIWEGIKNAGKGFLVSILDKVRCK 2419 2GHc (frog) VAGGCNP AP00586 Ref,
Temporin-GH FLPLLFGAISHLL 2420 (frog) AP00587 Ref, Brevinin-2TSa
GIMSLFKGVLKTAGKHVAGSLVD 2421 (frog) QLKCKITGGC AP00588 Ref,
Brevinin-1TSa FLGSIVGALASALPSLISKIRN 2422 (frog) AP00589 Ref,
Temporin- FLGALAKIISGIF 2423 1TSa (frog) AP00593 Ref, Brevinin-1CSa
FLPILAGLAAKIVPKLFCLATKKC 2424 (frog) AP00594 Ref, Temporin-
FLPIVGKLLSGLL 2425 1CSa (frog) AP00595 Ref, Temporin- FLPIIGKLLSGLL
2426 1CSb (frog) AP00596 Ref, Temporin- FLPLVTGLLSGLL 2427 1CSc
(frog) AP00597 Ref, Temporin- NFLGTLVNLAKKIL 2428 1CSd (frog)
AP00598 Ref, Temporin- FLSAITSLLGKLL 2429 1SPb (frog) AP00599 Ref,
Brevinin-2- GIWDTIKSMGKVFAGKILQNL 2430 related (frog) AP00600 Ref,
Odorranain- GLLRASSVWGRKYYVDLAGCAKA 2431 HP (frog) AP00601 Ref,
Brevinin- FLSLALAALPKFLCLVFKKC 2432 1DYa (frog) AP00602 Ref,
Brevinin- FLSLALAALPKLFCLIFKKC 2433 1DYb (frog) AP00603 Ref,
Brevinin- FLPLLLAGLPKLLCLFFKKC 2434 1DYc (frog) AP00607 Ref,
Brevinin- GLFDVVKGVLKGAGKNVAGSLLE 2435 2DYb (frog) QLKCKLSGGC
AP00608 Ref, Brevinin- GLFDVVKGVLKGVGKNVAGSLLE 2436 2DYc (frog)
QLKCKLSGGC AP00609 Ref, Brevinin- GIFDVVKGVLKGVGKNVAGSLLE 2437 2DYd
(frog) QLKCKLSGGC AP00610 Ref, Brevinin- GLFSVVTGVLKAVGKNVAKNVGG
2438 2DYe (frog) SLLEQLKCKISGGC AP00611 Ref, Temporin-
FIGPIISALASLFG 2439 1DYa (frog) AP00615 Ref, Palustrin-1b
ALFSILRGLKKLGNMGQAFVNCKI 2440 (frog) YKKC AP00616 Ref, Palustrin-1c
ALSILRGLEKLAKMGIALTNCKAT 2441 (frog) KKC AP00617 Ref, Palustrin-1d
ALSILKGLEKLAKMGIALTNCKAT 2442 (frog) KKC AP00619 Ref, Palustrin-2b
GFFSTVKNLATNVAGTVIDTLKCK 2443 (frog) VTGGCRS AP00620 Ref,
Palustrin-2c GFLSTVKNLATNVAGTVIDTLKCK 2444 (frog) VTGGCRS AP00621
Ref, Palustrin-3a GIFPKIIGKGIKTGIVNGIKSLVKGV 2445 (frog)
GMKVFKAGLNNIGNTGCNEDEC AP00622 Ref, Palustrin-3b
GIFPKIIGKGIKTGIVNGIKSLVKGV 2446 (frog) GMKVFKAGLSNIGNTGCNEDEC
AP00624 Ref, human ALL- ALLGDFFRKSKEKIGKEFKRIVQRI 2447 38 (an LL-37
KDFLRNLVPRTES analog released from its precursor hCAP-18 by
gastricsin in vivo) AP00625 Ref, human KR-20 KRIVQRIKDFLRNLVPRTES
2448 (KR20 from LL- 37) AP00626 Ref, human KS-30
KSKEKIGKEFKRIVQRIKDFLRNLV 2449 (KS30 from LL-37) PRTES AP00627 Ref,
human RK-31 RKSKEKIGKEFKRIVQRIKDFLRNL 2450 (RK31 from LL- VPRTES
37) AP00628 Ref, human LL-23 LLGDFFRKSKEKIGKEFKRIVQR 2451 (LL23
from LL-37) AP00629 Ref, human LL-29 LLGDFFRKSKEKIGKEFKRIVQRIK 2452
(LL29 from LL-37) DFLR AP00630 Ref, Amoeba
GEILCNLCTGLINTLENLLTTKGAD 2453 peptide (protozoan para AP00631 Ref,
Mundticin KYYGNGVSCNKKGCSVDWGKAIG 2454 (bacteria)
IIGNNSAANLATGGAAGWSK AP00638 Ref, Citropin 2.1
GLIGSIGKALGGLLVDVLKPKL 2455 (frog) AP00639 Ref, Citropin 2.1.3
GLIGSIGKALGGLLVDVLKPKLQA 2456 (frog) AS AP00640 Ref, Maculatin 1.3
GLLGLLGSVVSHVVPAIVGHF 2457 (frog) AP00641 Ref, Pardaxin 1
GFFALIPKIISSPLFKTLLSAVGSALS 2458 (Pardaxin P-1, SSGEQE Pardaxin P1,
Pa1, flat fish) AP00642 Ref, Pardaxin 2 GFFALIPKIISSPIFKTLLSAVGSALS
2459 (Pardaxin P-2, SSGGQE Pardaxin P2, Pa2, flat fish) AP00643
Ref, Pardaxin 3 GFFAFIPKIISSPLFKTLLSAVGSALS 2460 (Pardaxin P-3,
SSGEQE Pardaxin P3, Pa3, flat fish) AP00645 Ref, Pardaxin 5
GFFAFIPKIISSPLFKTLLSAVGSALS 2461 (Pardaxin P-5, SSGDQE Pardaxin P5,
Pa5, flat fish) AP00647 Ref, Brevinin-1PLb FLPLIAGLAANFLPKIFCAITKKC
2462 (frog) AP00648 Ref, Brevinin-1PLc FLPVIAGVAAKFLPKIFCAITKKC
2463 (frog) AP00649 Ref, Esculentin- GLFPKINKKKAKTGVFNIIKTVGKE 2464
1PLa (frog) AGMDLIRTGIDTIGCKIKGEC AP00650 Ref, Esculentin-
GIFTKINKKKAKTGVFNIIKTIGKEA 2465 1PLb (frog) GMDVIRAGIDTISCKIKGEC
AP00651 Ref, Esculentin- GLFSILKGVGKIALKGLAKNMGK 2466 2PLa (frog)
MGLDLVSCKISKEC AP00652 Ref, Ranatuerin- GIMDTVKNVAKNLAGQLLDKLKC
2467 2PLa (frog) KITAC AP00653 Ref, Ranatuerin-
GIMDTVKNAAKDLAGQLLDKLKC 2468 2PLb (frog) RITGC AP00654 Ref,
Ranatuerin- GLLDTIKNTAKNLAVGLLDKIKCK 2469 2PLc (frog) MTGC AP00655
Ref, Ranatuerin- GIMDSVKNVAKNIAGQLLDKLKC 2470 2PLd (frog) KITGC
AP00656 Ref, Ranatuerin- GIMDSVKNAAKNLAGQLLDTIKCK 2471 2PLe (frog)
ITAC AP00657 Ref, Ranatuerin- GIMDTVKNAAKDLAGQLDKLKCR 2472 2PLf
(frog) ITGC AP00658 Ref, Temporin- FLPLVGKILSGLI 2473 1PLa (frog)
AP00659 Ref, Ranatuerin 5 FLPIASLLGKYL 2474 (frog) AP00661 Ref,
Esculentin-2L GILSLFTGGIKALGKTLFKMAGKA 2475 (frog) GAEHLACKATNQC
AP00662 Ref, Esculentin-2B GLFSILRGAAKFASKGLGKDLTKL 2476
(ESC2B-RANBE, GVDLVACKISKQC frog) AP00663 Ref, Esculentin-2P
GFSSIFRGVAKFASKGLGKDLARL 2477 (frog) GVNLVACKISKQC AP00664 Ref,
Peptide A1 FLPAIAGILSQLF 2478 (frog) AP00665 Ref, Peptide B9
FLPLIAGLIGKLF 2479 (frog) AP00666 Ref, PG-L (frog) EGGGPQWAVGHFM
2480 AP00667 Ref, PG-KI (frog) EPHPDEFVGLM 2481 AP00668 Ref, PG-KII
(frog) EPNPDEFVGLM 2482 AP00669 Ref, PG-KIII (frog) EPHPNEFVGLM
2483 AP00670 Ref, PG-SPI (frog) EPNPDEFFGLM 2484 AP00660 Ref,
Pandinin 2 FWGALAKGALKLIPSLFSSFSKKD 2485
(African scorpion) AP00671 Ref, PG-SPII (frog) EPNPNEFFGLM 2486
AP00673 Ref, Lantibiotic WKSESVCTPGCVTGVLQTCFLQTI 2487 Ericin S
(bacteria TCNCHISK AP00674 Ref, Lantibiotic
VLSKSLCTPGCITGPLQTCYLCFPT 2488 Ericin A (bacteria FAKC AP00675 Ref,
Human beta FELDRICGYGTARCRKKCRSQEYRI 2489 defensin 4 (HBD-4,
GRCPNTYACCLRKWDESLLNRTKP HBD4, human defensin) AP00676 Ref, RL-37
(RL37, RLGNFFRKVKEKIGGGLKKVGQKI 2490 monkey KDFLGNLVPRTAS
cathelicidin) AP00677 Ref, CAP11 GLRKKFRKTRKRIQKLGRKIGKTG 2491
(Guinea pig RKVWKAWREYGQIPYPCRI cathelicidin) AP00678 Ref, Canine
RLKELITTGGQKIGEKIRRIGQRIKD 2492 cathelicidin FFKNLQPREEKS (K9CATH)
(dog) AP00679 Ref, Esculentin GLFSILKGVGKIAIKGLGKNLGKM 2493 2VEb
(frog) GLDLVSCKISKEC AP00680 Ref, SMAP-34 GLFGRLRDSLQRGGQKILEKAERI
2494 (sheep cathelicidin) WCKIKDIFR AP00681 Ref, OaBac5
RFRPPIRRPPIRPPFRPPFRPPVRPPIR 2495 (sheep cathelicidin)
PPFRPPFRPPIGPFP AP00682 Ref, OaBac6 RRLRPRHQHFPSERPWPKPLPLPLP 2496
(sheep cathelicidin) RPGPRPWPKPLPLPLPRPGLRPWPK PL AP00683 Ref,
OaBac7.5 RRLRPRRPRLPRPRPRPRPRPRSLPL 2497 (sheep cathelicidin)
PRPQPRRIPRPILLPWRPPRPIPRPQI QPIPRWL AP00684 Ref, OaBac11
RRLRPRRPRLPRPRPRPRPRPRSLPL 2498 (sheep cathelicidin)
PRPKPRPIPRPLPLPRPRPKPIPRPLP LPRPRPRRIPRPLPLPRPRPRPIPRPL
PLPQPQPSPIPRPL AP00685 Ref, Ranatuerin GIMDTVKGVAKTVAASLLDKLKC 2499
2VEb (frog) KITGC AP00686 Ref, eCATH-1 KRFGRLAKSFLRMRILLPRRKILLAS
2500 (horse cathelicidin) AP00687 Ref, eCATH-2
KRRHWFPLSFQEFLEQLRRFRDQL 2501 (horse cathelicidin) PFP AP00688 Ref,
eCATH-3 KRFHSVGSLIQRHQQMIRDKSEAT 2502 (horse cathelicidin)
RHGIRIITRPKLLLAS AP00689 Ref, Prophenin-1
AFPPPNVPGPRFPPPNFPGPRFPPPN 2503 (pig cathelicidin)
FPGPRFPPPNFPGPRFPPPNFPGPPFP PPIFPGPWFPPPPPFRPPPFGPPRFP AP00690 Ref,
Prophenin-2 AFPPPNVPGPRFPPPNVPGPRFPPPN 2504 (pig cathelicidin)
FPGPRFPPPNFPGPRFPPPNFPGPPFP PPIFPGPWFPPPPPFRPPPFGPPRFP AP00691 Ref,
HFIAP-1 GFFKKAWRKVKHAGRRVLDTAK 2505 (hagfish GVGRHYVNNWLNRYR
cathelicidin) AP00692 Ref, HFIAP-3 GWFKKAWRKVKNAGRRVLKGVG 2506
(hagfish IHYGVGLI cathelicidin) AP00693 Ref, Trout cath
RICSRDKNCVSRPGVGSIIGRPGGG 2507 (fish cathelicidin)
SLIGRPGGGSVIGRPGGGSPPGGGS FNDEFIRDHSDGNRFA AP00694 Ref, MRP
AIGSILGALAKGLPTLISWIKNR 2508 (melittin-related peptide) AP00695
Ref, Temporin- FLPILGKLLSGIL 2509 1TGa (frog) AP00696 Ref, Dahlein
1.1 GLFDIIKNIVSTL 2510 (frog) AP00697 Ref, Dahlein 1.2
GLFDIIKNIFSGL 2511 (frog) AP00698 Ref, Dahlein 4.1
GLWQLIKDKIKDAATGFVTGIQS 2512 (frog) AP00699 Ref, Dahlein 4.2
GLWQFIKDKLKDAATGLVTGIQS 2513 (frog) AP00700 Ref, Dahlein 4.3
GLWQFIKDKFKDAATGLVTGIQS 2514 (frog) AP00701 Ref, Dahlein 5.1
GLLGSIGNAIGAFIANKLKP 2515 (frog) AP00702 Ref, Dahlein 5.2
GLLGSIGNAIGAFIANKLKPK 2516 (frog) AP00703 Ref, Dahlein 5.3
GLLASLGKVLGGYLAEKLKP 2517 (frog) AP00704 Ref, Dahlein 5.4
GLLGSIGKVLGGYLAEKLKPK 2518 (frog) AP00705 Ref, Dahlein 5.5
GLLASLGKVLGGYLAEKLKPK 2519 (frog) AP00706 Ref, Dahlein 5.6
GLLASLGKVFGGYLAEKLKPK 2520 (frog) AP00709 Ref, Mytilus
GFGCPNDYPCHRHCKSIPGRAGGY 2521 defensin (mytilin) CGGAHRLRCTCYR A
(mollusc) AP00711 Ref, Mussel GFGCPNNYACHQHCKSIRGYCGG 2522 defensin
MGD2 YCAGWFRLRCTCYRCG AP00712 Ref, scorpion
GFGCPLNQGACHRHCRSIRRRGGY 2523 defensin CAGFFKQTCCYRN AP00713 Ref,
Androctonus GFGCPFNQGACHRHCRSIRRRGGY 2524 defensin CAGLFKQTCTCYR
AP00714 Ref, Orinthodoros GYGCPFNQYQCHSHCSGIRGYKGG 2525 defensin A
(soft YCKGTFKQTCKCY ticks) AP00715 Ref, VaD1 (plant
RTCMKKEGWGKCLIDTTCAHSCK 2526 defensin) NRGYIGGNCKGMTRTCYCLVNC
AP00722 Ref, Cryptonin GLLNGLALRLGKRALKKIIKRLCR 2527 (insect,
cicada) AP00723 Ref, Decoralin SLLSLLRKLIT 2528 (insect) AP00724
Ref, RTD-2 (rhesus RCLCRRGVCRCLCRRGVC 2529 theta-defensin-2,
minidefensin, XXC, BBS, lectin, ZZHa) AP00725 Ref, RTD-3 (rhesus
RCICTRGFCRCICTRGFC 2530 theta-defensin-3, minidefensin, XXC, BBS,
lectin, ZZHa) AP00726 Ref, Combi-1 RRWWRF 2531 (synthetic) AP00748
Ref, Gm pro-rich DIQIPGIKKPTHRDIIIPNWNPNVRT 2532 pept1 (insect)
QPWQRFGGNKS AP00749 Ref, Gm anionic EADEPLWLYKGDNIERAPTTADHP 2533
pept 1 (insect) ILPSIIDDVKLDPNRRYA AP00750 Ref, Gm pro-rich
EIRLPEPFRFPSPTVPKPIDIDPILPHP 2534 pept 2 (insect) WSPRQTYPIIARRS
AP00752 Ref, Gm defensin- DKLIGSCVWGATNYTSDCNAECK 2535 like peptide
(insect) RRGYKGGHCGSFWNVNCWCEE AP00753 Ref, Gm
VQETQKLAKTVGANLEETNKKLA 2536 apolipophoricin
PQIKSAYDDFVKQAQEVQKKLHE (insect) AASKQ AP00754 Ref, Gm anionic
ETESTPDYLKNIQQQLEEYTKNFNT 2537 pept2 (insect)
QVQNAFDSDKIKSEVNNFIESLGKI LNTEKKEAPK AP00755 Ref, Gm cecropin
ENFFKEIERAGQRIRDAIISAAPAVE 2538 D-like pept, insect TLAQAQKIIKGGD
AP00756 Ref, Dermaseptin- ALWKDILKNAGKAALNEINQLVNQ 2539 B6 (DRS-B6,
DRS B6, XXA, frog) AP00759 Ref, Phylloseptin- FLSLIPHAINAVSTLVHHSG
2540 O1 (PLS-O1, Phylloseptin-4, PS- 4, XXA, frog) AP00760 Ref,
Phylloseptin- FLSLIPHAINAVSAIAKHS 2541 O2 (PLS-O2, Phylloseptin-5,
PS- 5, XXA, frog) AP00761 Ref, Phylloseptin-6 SLIPHAINAVSAIAKHF
2542 (Phylloseptin-H4, PLS-H4, PS-6, XXA, frog) AP00762 Ref,
Phylloseptin-7 FLSLIPHAINAVSAIAKHF 2543 (Phylloseptin-H5, PLS-H5,
PS-7, XXA, frog) AP00763 Ref, Dermaseptin GLWSTIKNVGKEAAIAAGKAALG
2544 DPh-1 (XXA, frog) AL AP00764 Ref, Dermaseptin-
GLRSKIWLWVLLMIWQESNKFKKM 2545 S9 (DRS-S9, DRS S9, frog) AP00765
Ref, Human salvic MHDFWVLWVLLEYIYNSACSVLS 2546
ATSSVSSRVLNRSLQVKVVKITN AP00766 Ref, Gassericin A
IYWIADQFGIHLATGTARKLLDAM 2547 (XXC, XXD2, ASGASLGTAFAAILGVTLPAWALA
class IV AAGALGATAA bacteriocin, Gram- positive bacteria) AP00767
Ref, Circularin A VAGALGVQTAAATTIVNVILNAGT 2548 (XXC, class IV
LVTVLGIIASIASGGAGTLMTIGWA bacteriocin, Gram- TFKATVQKLAKQSMARAIAY
positive bacteria) AP00768 Ref, Closticin 574
PNWTKIGKCAGSIAWAIGSGLFGG 2549 (bacteria) AKLIKIKKYIAELGGLQKAAKLLV
GATTWEEKLHAGGYALINLAAELT GVAGIQANCF AP00769 Ref, Caerin 1.11
GLLGAMFKVASKVLPHVVPAITEHF 2550 (XXA, frog) AP00770 Ref, Maculatin
1.4 GLLGLLGSVVSHVLPAITQHL 2551 (XXA, frog) AP00771 Ref, Magainin 1
GIGKFLHSAGKFGKAFVGEIMKS 2552 (frog) AP00772 Ref, Oxyopinin 1
FRGLAKLLKIGLKSFARVLKKVLP 2553 (spider) KAAKAGKALAKSMADENAIRQQNQ
AP00773 Ref, Oxyopinin 2a GKFSVFGKILRSIAKVFKGVGKVR 2554 (spider)
KQFKTASDLDKNQ AP00774 Ref, Oxyopinin 2b GKFSGFAKILKSIAKFFKGVGKVR
2555
(spider) KGFKEASDLDKNQ AP00775 Ref, Oxyopinin 2c
GKLSGISKVLRAIAKFFKGVGKAR 2556 (spider) KQFKEASDLDKNQ AP00776 Ref,
Oxyopinin 2d GKFSVFSKILRSIAKVFKGVGKVRK 2557 (spider) GFKTASDLDKNQ
AP00777 Ref, NRC-1 (XXA, GKGRWLERIGKAGGIIIGGALDHL 2558 fish, gene
predicted) AP00778 Ref, NRC-2 (XXA, WLRRIGKGVKIIGGAALDHL 2559 fish,
gene predicted) AP00779 Ref, NRC-3 (XXA, GRRKRKWLRRIGKGVKIIGGAALD
2560 fish, gene HL predicted) AP00781 Ref, NRC-5 (XXA,
FLGALIKGAIHGGRFIHGMIQNHH 2561 fish, gene predicted) AP00782 Ref,
NRC-6 (XXA, GWGSIFKHGRHAAKHIGHAAVNH 2562 fish, gene YL predicted)
AP00783 Ref, NRC-7 (XXA, RWGKWFKKATHVGKHVGKAALT 2563 fish, gene AYL
predicted) AP00784 Ref, NRC-10 FFRLLFHGVHHVGKIKPRA 2564 (XXA, fish,
gene predicted) AP00785 Ref, NRC-11 GWKSVFRKAKKVGKTVGGLALD 2565
(XXA, fish, gene HYL predicted) AP00786 Ref, NRC-12
GWKKWFNRAKKVGKTVGGLAVD 2566 (XXA, fish, gene HYL predicted) AP00787
Ref, NRC-13 GWRLLLKKAEVKTVGKLALKHYL 2567 (XXA, fish, gene
predicted) AP00788 Ref, NRC-14 AGWGSIFKHIFKAGKFIHGAIQAHND 2568
(XXA, fish, gene predicted) AP00789 Ref, NRC-15
GFWGKLFKLGLHGIGLLHLHL 2569 (XXA, fish, gene predicted) AP00790 Ref,
NRC-16 GWKKWLRKGAKHLGQAAIK 2570 (XXA, fish, gene predicted) AP00791
Ref, NRC-17 GWKKWLRKGAKHLGQAAIKGLAS 2571 (XXA, fish, gene
predicted) AP00792 Ref, NRC-19 FLGLLFHGVHHVGKWIHGLIHGHH 2572 (XXA,
fish, gene predicted) AP00793 Ref, Bombinin H2 IIGPVLGLVGSALGGLLKKI
2573 (XXA, frog) AP00794 Ref, Bombinin H3 IIGPVLGMVGSALGGLLKKI 2574
(frog, XXD, XXA) AP00795 Ref, Bombinin H7 ILGPILGLVSNALGGLL 2575
(frog, XXD, XXA) AP00796 Ref, Bombinin GH- IIGPVLGLVGKPLESLLE 2576
1L (XXA, toad) AP00797 Ref, Bombinin GH- IIGPVLGLVGKPLESLLE 2577 1D
(toad, XXD, XXA) AP00807 Ref, Enterocin E- NRWYCNSAAGGVGGAAGCVLAG
2578 760 (bacteriocin, YVGEAKENIAGEVRKGWGMAGGF bacteria)
THNKACKSFPGSGWASG AP00808 Ref, hepcidin (fish) CRFCCRCCPRMRGCGLCCRF
2579 AP00809 Ref, hepcidin TH1- GIKCRFCCGCCTPGICGVCCRF 2580 5
(fish) AP00810 Ref, hepcidin TH2- QSHLSLCRWCCNCCRSNKGC 2581 3
(fish) AP00811 Ref, human LEAP-2 MTPFWRGVSLRPIGASCRDDSECIT 2582
RLCRKRRCSLSVAQE AP00812 Ref, Enkelytin FAEPLPSEEEGESYSKEPPEMEKRY
2583 (cow) GGFM AP00732 Ref, Spheniscin-1 SFGLCRLRRGSCAHGRCRFPSIPIG
2584 (Sphe-1, avian RCSRFVQCCRRVW defensin) AP00733 Ref, Organgutan
LLGDFFRKAREKIGEEFKRIVQRIK 2585 ppyLL-37 (Great DFLRNLVPRTES Ape,
primate cathelicidin) AP00734 Ref, Gibbon SLGNFFRKARKKIGEEFKRIVQRIK
2586 hmdSL-37 DFLQHLIPRTEA (hylobatidae, primate cathelicidin)
AP00735 Ref, pobRL-37 RLGNFFRKAKKKIGRGLKKIGQKI 2587
(cercopithecidae, KDFLGNLVPRTES primate cathelicidin) AP00736 Ref,
cjaRL-37 RLGDILQKAREKIEGGLKKLVQKI 2588 (primate KDFFGKFAPRTES
cathelicidin) AP00737 Ref, Plasticin GLVTSLIKGAGKLLGGLFGSVTG 2589
PBN2KF (XXA, DRP-PBN2, frog) AP00738 Ref, Plasticin
GLVTGLLKTAGKLLGDLFGSLTG 2590 ANCKF (XXA, synthetic) AP00739 Ref,
Plasticin GVVTDLLKTAGKLLGNLFGSLSG 2591 PD36KF (XXA, synthetic)
AP00740 Ref, Plasticin GVVTDLLKTAGKLLGNLVGSLSG 2592 PD36K (XXA,
synthetic) AP00741 Ref, Chicken PITYLDAILAAVRLLNQRISGPCILR 2593
cathelicidin-B1 LREAQPRPGWVGTLQRRREVSFLV (bird cathelicidin)
EDGPCPPGVDCRSCEPGALQHCVG TVSIEQQPTAELRCRPLRPQ AP00742 Ref, Chicken
MRILYLLLSVLFVVLQGVAGQPYF 2594 gallinacin 4 (Gal 4)
SSPIHACRYQRGVCIPGPCRWPYY RVGSCGSGLKSCCVRNRWA AP00743 Ref, Chicken
MKILCFFIVLFVAVHGAVGFSRSPR 2595 gallinacin 7 (Gal 7)
YHMQCGYRGTFCTPGKCPYGNAY LGLCRPKYSCCRWL AP00744 Ref, Chicken
MQILPLLFAVLLLMLRAEPGLSLA 2596 gallinacin 9 (Gal 9)
RGLPQDCERRGGFCSHKSCPPGIGR IGLCSKEDFCCRSRWYS AP00745 Ref, Chicken
MTPFWRGVSLRPVGASCRDNSECI 2597 LEAP-2 (cLEAP- TMLCRKNRCFLRTASE 2)
AP00814 Ref, Caerulein GLGSILGKILNVAGKVGKTIGKVA 2598
precursor-related DAVGNKE fragment Ea (CPRF-Ea, frog) AP00815 Ref,
Caerulein GLGSFLKNAIKIAGKVGSTIGKVAD 2599 precursor-related AIGNKE
fragment Eb (CPRF-Eb, frog) AP00816 Ref, Caerulein
GLGSFFKNAIKIAGKVGSTIGKVAD 2600 precursor-related AIGNKE fragment Ec
(CPRF-Ec, frog) AP00817 Ref, Temporin-1Oa FLPLLASLFSRLL 2601 (frog)
AP00818 Ref, Temporin-1Ob FLPLIGKILGTIL 2602 (frog) AP00819 Ref,
Temporin-1Oc FLPLLASLFSRLF 2603 (frog) AP00820 Ref, Temporin-1Od
FLPLLASLFSGLF 2604 (frog) AP00821 Ref, Brevinin-20a
GLFNVFKGLKTAGKHVAGSLLNQ 2605 (frog) LKCKVSGGC AP00822 Ref,
Brevinin-20b GIFNVFKGALKTAGKHVAGSLLNQ 2606 (frog) LKCKVSGEC AP00824
Ref, Temporin-1Gb SILPTIVSFLSKFL 2607 (XXA, frog) AP00825 Ref,
Temporin-1Gc SILPTIVSFLTKFL 2608 (XXA, frog) AP00826 Ref,
Temporin-1Gd FILPLIASFLSKFL 2609 (XXA, frog) AP00827 Ref,
Ranatuerin- SMISVLKNLGKVGLGFVACKVNK 2610 1Ga (frog) QC AP00829 Ref,
Ranalexin-1G FLGGLMKIIPAAFCAVTKKC 2611 (frog) AP00830 Ref,
Ranatuerin-2G GLLLDTLKGAAKDIAGIALEKLKC 2612 (frog) KITGCKP AP00831
Ref, Odorranain- GLLSGILGAGKHIVCGLTGCAKA 2613 NR (frog) AP00832
Ref, Maximin H1 ILGPVISTIGGVLGGLLKNL 2614 (XXA, toad) AP00834 Ref,
G. mellonella KVNANAIKKGGKAIGKGFKVISAA 2615 moricin-like
STAHDVYEHIKNRRH peptide A (Gm- mlpA, insect) AP00835 Ref, G.
mellonella GKIPVKAIKKGGQIIGKALRGINIAS 2616 moricin-like
TAHDIISQFKPKKKKNH peptide B (Gm- mlpB, insect) AP00836 Ref, G.
mellonella KVPIGAIKKGGKIIKKGLGVIGAAG 2617 moricin-like
TAHEVYSHVKNRH peptide C1 (Gm- mlpC1, insect) AP00837 Ref, G.
mellonella KVPIGAIKKGGKIIKKGLGVLGAA 2618 moricin-like
GTAHEVYNHVRNRQ peptide C2 (Gm- mlpC2, insect) AP00838 Ref, G.
mellonella KVPIGAIKKGGKIIKKGLGVIGAAG 2619 moricin-like
TAHEVYSHVKNRQ peptide C3 (Gm- mlpC3, insect) AP00839 Ref, G.
mellonella KVPVGAIKKGGKAIKTGLGVVGA 2620 moricin-like
AGTAHEVYSHIRNRH peptide C4/C5 (Gm-mlpC4/C5, insect)
AP00840 Ref, G. mellonella KGIGSALKKGGKIIKGGLGALGAIG 2621
moricin-like TGQQVYEHVQNRQ peptide D (Gm- mlpD, insect) AP00841
Ref, Enterocin A TTHSGKYYGNGVYCTKNKCTVD 2622 (EntA, class IIA
WAKATTCIAGMSIGGFLGGAIPGKC bacteriocin, i.e. pediocin-like peptide,
bacteria) AP00842 Ref, Divercin V41 TKYYGNGVYCNSKKCWVDWGQA 2623
(DvnV41, class IIa SGCIGQTVVGGWLGGAIPGKC bacteriocin, pediocin-like
peptide, bacteria. DvnRV41 is the recombinant form) AP00843 Ref,
Divergicin TKYYGNGVYCNSKKCWVDWGTA 2624 M35 (class IIa
QGCIDVVIGQLGGGIPGKGKC bacteriocin, pediocin-like peptide, bacteria)
AP00844 Ref, Coagulin KYYGNGVTCGKHSCSVDWGKATT 2625 (bacteriocin,
CIINNGAMAWATGGHQGTHKC pediocin-like peptide, bacteria) AP00845 Ref,
Listeriocin KSYGNGVHCNKKKCWVDWGSAIS 2626 743A (class IIa
TIGNNSAANWATGGAAGWKS bacteriocin, pediocin-like peptide, bacteria)
AP00846 Ref, Mundticin KS KYYGNGVSCNKKGCSVDWGKAIG 2627 (enterocin
CRL35, IIGNNSAANLATGGAAGWKS mundticin ATO6, mundticin QU2, class
IIa bacteriocin, pediocin-like peptide, bacteria) AP00847 Ref,
Sakacin 5X KYYGNGLSCNKSGCSVDWSKAISII 2628 (Sak5X, class IIa
GNNAVANLTTGGAAGWKS bacteriocin, pediocin-like peptide, bacteria)
AP00848 Ref, Leucocin C KNYGNGVHCTKKGCSVDWGYAW 2629 (class IIa
ANIANNSVMNGLTGGNAGWHN bacteriocin, pediocin-like peptide, bacteria)
AP00849 Ref, Lactococcin TSYGNGVHCNKSKCWIDVSELETY 2630 MMFII (class
IIa KAGTVSNPKDILW bacteriocin, pediocin-like peptide, bacteria)
AP00850 Ref, Sakacin G KYYGNGVSCNSHGCSVNWGQAW 2631 (SakG, class IIa
TCGVNHLANGGHGVC bacteriocin, pediocin-like peptide, bacteria)
AP00851 Ref, Plantaricin KYYGNGVTCGKHSCSVNWGQAFS 2632 423 (class
IIa CSVSHLANFGHGKC bacteriocin, pediocin-like peptide, bacteria)
AP00852 Ref, Plantaricin KYYGNGLSCSKKGCTVNWGQAFS 2633 C19 (class
IIa CGVNRVATAGHHKC bacteriocin, pediocin-like peptide, bacteria)
AP00853 Ref, Enterocin P ATRSYGNGVYCNNSKCWVNWGE 2634 (EntP, class
IIa AKENIAGIVISGWASGLAGMGH bacteriocin, pediocin-like peptide,
bacteria) AP00854 Ref, Bacteriocin 31 ATYYGNGLYCNKQKCWVDWNKA 2635
(Bac 31, Bac31, SREIGKIIVNGWVQHGPWAPR class IIa bacteriocin,
pediocin-like peptide, bacteria) AP00855 Ref, MSI-78
GIGKFLKKAKKFGKAFVKILKK 2636 (XXA, synthetic) AP00856 Ref, MSI-594
GIGKFLKKAKKGIGAVLKVLTTGL 2637 (XXA, synthetic) AP00857 Ref,
Catestatin SSMKLSFRARAYGFRGPGPQL 2638 (human CHGA(352-372), human
Cst) AP00858 Ref, Temporin D LLPIVGNLLNSLL 2639 (XXA, frog) AP00859
Ref, Temporin H LSPNLLKSLL 2640 (XXA, frog) AP00861 Ref,
Brevinin-ALb FLPLAVSLAANFLPKLFCKITKKC 2641 (frog) AP00862 Ref,
Brevinin 1E FLPLLAGLAANFLPKIFCKITKRC 2642 (frog) AP00863 Ref,
Temporin- FLPIVGKLLSGLSGLL 2643 ALa (XXA, frog) AP00864 Ref,
Temporin FLPIVGRLISGLL 2644 1ARa (XXA, frog) AP00865 Ref, Temporin
FLPIIGQLLSGLL 2645 1AUa (XXA, Temporin-1AUa) (frog) AP00866 Ref,
Temporin FLPIIAKVLSGLL 2646 1Bya (XXA, Temporin-1Bya, frog) AP00867
Ref, Temporin 1Ec FLPVIAGLLSKLF 2647 (XXA, frog) AP00869 Ref,
Temporin 1Ja ILPLVGNLLNDLL 2648 (XXA, Temporin- 1Ja, frog) AP00873
Ref, Temporin 1Pra ILPILGNLLNGLL 2649 (XXA, frog) AP00874 Ref,
Temporin 1VE FLPLVGKILSGLI 2650 (XXA, frog) AP00875 Ref, Temporin
1Va FLSSIGKILGNLL 2651 (XXA, frog) AP00876 Ref, Temporin 1Vb
FLSIIAKVLGSLF 2652 (XXA, frog) AP00877 Ref, Brevinin-1Ja
FLGSLIGAAIPAIKQLLGLKK 2653 (frog) AP00878 Ref, Brevinin-
FLPILASLAAKFGPKLFCLVTKKC 2654 1BYa (frog) AP00884 Ref, Ixosin-B
(tick) QLKVDLWGTRSGIQPEQHSSGKSD 2655 VRRWRSRY AP00885 Ref,
Brevinin- FLPILASLAAKLGPKLFCLVTKKC 2656 1BYb (frog) AP00886 Ref,
Brevinin- FLPILASLAATLGPKLLCLITKKC 2657 1BYc (frog) AP00887 Ref,
Brevinin- GILSTFKGLAKGVAKDLAGNLLDK 2658 2BYa (frog) FKCKITGC
AP00888 Ref, Brevinin- GIMDSVKGLAKNLAGKLLDSLKC 2659 2BYb (frog)
KITGC AP00891 Ref, Pilosulin 3 IIGLVSKGTCVLVKTVCKKVLKQG 2660 (Myr b
III)(ants) AP00892 Ref, Pilosulin 4 PDITKLNIKKLTKATCKVISKGASM 2661
(Myr b IV)(ants) CKVLFDKKKQE AP00893 Ref, Pilosulin 5
DVKGMKKAIKGILDCVIEKGYDKL 2662 (Myr b III)(ants) AAKLKKVIQQLWE
AP00894 Ref, Ocellatin 4 GLLDFVTGVGKDIFAQLIKQI 2663 (XXA, frog)
AP00895 Ref, OH-CATH KRFKKFFKKLKNSVKKRAKKFFK 2664 (snake
cathelicidin, KPRVIGVSIPF reptile cathelicidin, or elapid
cathelicidins) AP00896 Ref, BF-CATH KRFKKFFKKLKKSVKKRAKKFFK 2665
(snake cathelicidin) KPRVIGVSIPF AP00897 Ref, NA-CATH
KRFKKFFKKLKNSVKKRAKKFFK 2666 (snake cathelicidin) KPKVIGVTFPF
AP00898 Ref, Temporin-1Sa FLSGIVGMLGKLF 2667 (XXA, frog) AP00899
Ref, Temporin-1Sb FLPIVTNLLSGLL 2668 (XXA, frog) AP00900 Ref,
Temporin-1Sc FLSHIAGFLSNLF 2669 (XXA, frog) AP00913 Ref, Ib-AMP1
EWGRRCCGWGPGRRYCVRWC 2670 (IbAMP1, plant defensin) AP00914 Ref,
Ib-AMP2 QYGRRCCNWGPGRRYCKRWC 2671 (IBAMP2, plant defensin) AP00915
Ref, Ee-CBP QQCGRQAGNRRCANNLCCSQYGY 2672 (EeCBP, plant
CGRTNEYCCTSQGCQSQCRRCG defensin, hevein- type, E. europaeus
chitin-binding protein) AP00916 Ref, Pa-AMP1
AGCIKNGGRCNASAGPPYCCSSYC 2673 (PaAMP1, plant FQIAGQSYGVCKNR
defensin, C6 type) AP00917 Ref, Pa-AMP2 ACIKNGGRCVASGGPPYCCSNYCL
2674 (PaAMP2, plant QIAGQSYGVCKKH defensin, C6 type) AP00924 Ref,
Ornithodoros GYGCPFNQYQCHSHCRGIRGYKG 2675 defensin B (soft
GYCTGRFKQTCKCY ticks) AP00925 Ref, Ornithodoros
GYGCPFNQYQCHSHCSGIRGYKGG 2676 defensin C (soft YCKGLFKQTCNCY ticks)
AP00926 Ref, Ornithodoros GFGCPFNQYECHAHCSGVPGYKG 2677 defensin D
(soft GYCKGLFKQTCNCY ticks) AP00927 Ref, IYFIADKMGIQLAPAWYQDIVNWV
2678 Butyrivibriocin SAGGTLTTGFAIIVGVTVPAWIAEA AR10 (XXC, class
AAAFGIASA IV bacteriocin, gram-positive bacteria) AP00929 Ref,
AS-48 ASLQFLPIAHMAKEFGIPAAVAGT 2679 (enterocin 4, XXC,
VINVVEAGGWVTTIVSILTAVGSG class IV bacteriocin
GLSLLAAAGRESIKAYLKKEIKKK
or class IId GKRAVIAW bacteriocin, Gram- positive bacteria) AP00930
Ref, Reutericin 6 IYWIADQFGIHLATGTARKLLDAM 2680 (XXC, XXD1,
ASGASLGTAFAAILGVTLPAWALA class IV AAGALGATAA bacteriocin, Gram-
positive bacteria) AP00931 Ref, Uberolysin LAGYTGIASGTAKKVVDAIDKGAA
2681 (XXC, class IV AFVIISIISTVISAGALGAVSASADFI bacteriocin, Gram-
ILTVKNYISRNLKAQAVIW positive bacteria) AP00932 Ref, Acidocin B
IYWIADQFGIHLATGTARKLLDAV 2682 (XXC, class IV
ASGASLGTAFAAILGVTLPAWALA bacteriocin, Gram- AAGALGATAA positive
bacteria) AP00980 Ref, Phormia ATCDLLSGTGINHSACAAHCLLRG 2683
defensin B (insect NRGGYCNRKGVCVCRN defensin B) AP00990 Ref,
Pth-St1 (plant RNCESLSHRFKGPCTRDSN 2684 defensin) AP00991 Ref,
Snakin-1 GSNFCDSKCKLRCSKAGLADRCLK 2685 (StSN1, plant
YCGICCEECKCVPSGTYGNKHECP defensin) CYRDKKNSKGKSKCP AP00992 Ref,
Snakin-2 YSYKKIDCGGACAARCRLSSRPRL 2686 (StSN2, plant
CNRACGTCCARCNCVPPGTSGNTE defensin) TCPCYASLTTHGNKRKCP AP00993 Ref,
So-D2 (S. oleracea GIFSSRKCKTPSKTFKGICTRDSNC 2687 defensin
DTSCRYEGYPAGDCKGIRRRCMCS D2, plant defensin) KPC AP00994 Ref, So-D6
(S. oleracea GIFSNMYARTPAGYFRGP 2688 defensin D6, plant defensin)
AP00997 Ref, Nisin Q ITSISLCTPGCKTGVLMGCNLKTAT 2689 (lantibiotic,
CNCSVHVSK bacteriocins, bacteria) AP01008 Ref, Tachystatin
YSRCQLQGFNCVVRSYGLPTIPCC 2690 A1 (BBS, RGLTCRSYFPGSTYGRCQRF
horseshoe crabs) AP01009 Ref, Tachystatin C DYDWSLRGPPKCATYGQKCRTWS
2691 (BBS, horseshoe PRNCCWNLRCKAFRCRPR crabs) AP01012 Ref,
Latarcin 3a SWKSMAKKLKEYMEKLKQRA 2692 (Ltc3a, XXA, BBM, spider)
AP01013 Ref, Latarcin 3b SWASMAKKLKEYMEKLKQRA 2693 (Ltc3b, XXA,
BBM, spider) AP01014 Ref, Latarcin 4a GLKDKFKSMGEKLKQYIQTWKAKF 2694
(Ltc4a, XXA, BBM, spider) AP01015 Ref, Latarcin 4b
SLKDKVKSMGEKLKQYIQTWKAKF 2695 (Ltc4b, XXA, BBM, spider) AP01016
Ref, Latarcin 5 GFFGKMKEYFKKFGASFKRRFANL 2696 (Ltc5, XXA, BBM, KKRL
spider) AP01018 Ref, Latarcin 6a QAFQTFKPDWNKIRYDAMKMQTS 2697
(Ltc6a, BBM, LGQMKKRFNL spider) AP01019 Ref, Latarcin 7
GETFDKLKEKLKTFYQKLVEKAED 2698 (Ltc7, BBM, LKGDLKAKLS spider)
AP01049 Ref, Kalata B2 VCGETCFGGTCNTPGCSCTWPICT 2699 (plant
cyclotides, RDGLP XXC) AP01141 Ref, Cryptdin-6
LRDLVCYCRARGCKGRERMNGTC 2700 (Crp6, animal RKGHLLYMLCCR defensin,
alpha, mouse) AP01142 Ref, Rabbit kidney KPYCSCKWRCGIGEEEKGICHKFPI
2701 defensin RK-2 VTYVCCRRP (animal defensin, alpha-defensin)
AP01146 Ref, Gallinacin 6 DTLACRQSHGSCSFVACRAPSVDI 2702 (Gal6,
Gal-6, avian GTCRGGKLKCCKWAPSS beta defensin, bird) AP01147 Ref,
Gallinacin 8 DTVACRIQGNFCRAGACPPTFTISG 2703 (Gal8, Gal-8, avian
QCHGGLLNCCAKIPAQ beta defensin, bird) AP01148 Ref, Gallinacin 3
IATQCRIRGGFCRVGSCRFPHIAIGK 2704 (Gal3, Gal-3, avian CATFISCCGRAY
beta defensin, bird) AP01152 Ref, Lactococcin Q
SIWGDIGQGVGKAAYWVGKAMG 2705 (class IIb NMSDVNQASRINRKKKH
bacteriocin, bacteria, chain a. For chain b, see Info) AP01155 Ref,
Enterocin ESVFSKIGNAVGPAAYWILKGLGN 2706 1071 (Ent1071A,
MSDVNQADRINRKKH class IIb bacteriocin, bacteria; chain B is
Enterocin 1071B or Ent1071B, see info) AP01156 Ref, Plantaricin S
NKLAYNMGHYAGKATIFGLAAW 2707 (chain a, class IIb ALLA bacteriocin,
bacteria) AP01159 Ref, Hinnavin II KWKIFKKIEHMGQNIRDGLIKAGP 2708
(Hin II, XXA, AVQVVGQAATIYK insect) AP01160 Ref, NK-2
KILRGLCKKIMRSFLRRISWDILTG 2709 (synthetic, XXA) KK AP01167 Ref,
Plantaricin LTTKLWSSWGYYLGKKARWNLK 2710 NC8 (PLNC8, HPYVQF chain a,
class IIb bacteriocin, bacteria. For chain b, see Info) AP01168
Ref, Carnocyclin A LVAYGIAQGTAEKVVSLINAGLTV 2711 (a circular
GSIISILGGVTVGLSGVFTAVKAAI bacteriocin, XXC, AKQGIKKAIQL bacteria)
AP01169 Ref, Lactacin F NRWGDTVLSAASGAGTGIKACKSF 2712 (LafX, class
IIb GPWGMAICGVGGAAIGGYFGYTHN bacteriocin, bacteria. For LafA, see
Info) AP01170 Ref, Brochocin C YSSKDCLKDIGKGIGAGTVAGAAG 2713 (BrcC,
chain BrcA, GGLAAGLGAIPGAFVGAHFGVIGG class IIb SAACIGGLLGN
bacteriocin, bacteria. For BrcB, see Info) AP01171 Ref,
Thermophilin YSGKDCLKDMGGYALAGAGSGAL 2714 13 (chain a ThmA,
WGAPAGGVGALPGAFVGAHVGAI 2-chain class IIb AGGFACMGGMIGNKFN
bacteriocin, bacteria. For chain B ThmB, see Info) AP01172 Ref,
ABP-118 KRGPNCVGNFLGGLFAGAAAGVP 2715 (chain a:
LGPAGIVGGANLGMVGGALTCL Abp118alpha, class IIb bacteriocin,
bacteria. For chain b: Abp118beta, see Info) AP01173 Ref,
Salivaricin P KRGPNCVGNFLGGLFAGAAAGVP 2716 (chain a: Sln1;
LGPAGIVGGANLGMVGGALTCL class IIb bacteriocin, bacteria. For chain
b: Sln2, see Info) AP01174 Ref, Mutacin IV KVSGGEAVAAIGICATASAAIGGL
2717 (chain a: NlmA, AGATLVTPYCVGTWGLIRSH class IIb bacteriocin,
bacteria. For chain b: NLmB, see Info) AP01175 Ref, Lactocin 705
GMSGYIQGIPDFLKGYLHGISAAN 2718 (chain a: KHKKGRLGY Lac705alpha;
class IIb bacteriocin, bacteria. For chain b: Lac705beta, see Info)
AP01176 Ref, Cytolysin TTPACFTIGLGVGALFSAKFC 2719 (CylLS, bacteria;
Chain B: CylLL) AP01177 Ref, Plantaricin EF FNRGGYNFGKSVRHVVDAIGSVA
2720 (chain a. PlnE, GILKSIR class IIb bacteriocin, bacteria. Chain
b: PlnF) AP01178 Ref, Plantaricin JK GAWKNFWSSLRKGFYDGEAGRAI 2721
(chain a: PlnJ; class RR IIb bacteriocin, bacteria. Chain b: PlnK)
AP01179 Ref, Enterocin SE- NGVYCNKQKCWVDWSRARSEIID 2722 K4 (class
IIa RGVKAYVNGFTKVLGGIGGR bacteriocin, bacteria) AP01180 Ref,
Acidocin NPKVAHCASQIGRSTAWGAVSGA 2723 J1132 (class IIb bacteriocin,
bacteria) AP01181 Ref, Curvaticin AYPGNGVHCGKYSCTVDKQTAIG 2724 L442
(class IIa NIGNNAA bacteriocin, bacteria) AP01182 Ref, Bacteriocin
32 FTPSVSFSQNGGVVEAAAQRGYIY 2725 (Bac 32, class IIa
KKYPKGAKVPNKVKMLVNIRGKQ bacteriocin, TMRTCYLMSWTASSRTAKYYYYI
bacteria) AP01183 Ref, Bacteriocin 43 ATYYGNGLYCNKEKCWVDWNQA 2726
(Bac 43, KGEIGKIIVNGWVNHGPWAPRR bacteriocin, bacteria) AP01184 Ref,
Bacteriocin T8 ATYYGNGLYCNKEKCWVDWNQA 2727 (Bac T8, class IIa
KGEIGKIIVNGWVNHGPWAPRR bacteriocin, bacteria) AP01185 Ref,
Enterocin B ENDHRMPNNLNRPNNLSKGGAKC 2728 (EntB, bacteriocin,
GAAIAGGLFGIPKGPLAWAAGLAN bacteria) VYSKCN
AP01186 Ref, Acidocin A KTYYGTNGVHCTKKSLWGKVRLK 2729 (bacteriocin,
NVIPGTLCRKQSLPIKQDLKILLGW bacteria) ATGAFGKTFH AP01187 Ref,
Enterocin Q MNFLKNGIAKWMTGAELQAYKK 2730 (EntQ, class IIc
KYGCLPWEKISC bacteriocin, leaderless, i.e. no signal peptide,
bacteria) AP01188 Ref, Enterocin MLAKIKAMIKKFPNPYTLAAKLTT 2731 EJ97
(EntEJ97, YEINWYKQQYGRYPWERPVA class IIc bacteriocin, leaderless,
i.e. no signal peptide, bacteria) AP01189 Ref, Enterocin RJ-
APAGLVAKFGRPIVKKYYKQIMQF 2732 11 (EntRJ-11, class
IGEGSAINKIIPWIARMWRT IIc bacteriocin, leaderless, i.e. no signal
sequence, bacteria) AP01190 Ref, Enterocin L50
MGAIAKLVAKFGWPIVKKYYKQI 2733 (old name: MQFIGEGWAINKIIEWIKKHI
pediocin L50, EntL50A, a two- chain class IIc bacteriocin,
leaderless, i.e. no signal peptide, bacteria. The sequence of
EntL50B is provided in Info) AP01191 Ref, MR10
MGAIAKLVAKFGWPIVKKYYKQI 2734 (MR10A, class IIc
MQFIGEGWAINKIIDWIKKHI bacteriocin, leaderless, i.e. no signal
peptide, bacteria. For the sequence of chain b, see Info) AP01192
Ref, Halocin S8 SDCNINSNTAADVILCFNQVGSCA 2735 (HalS8, LCSPTLVGGPVP
microhalocin, archaeocins, archeae) AP01193 Ref, Halocin C8
DIDITGCSACKYAAGQVCTIGCSA 2736 (HalC8, AGGFICGLLGITIPVAGLSCLGFVEI
microhalocins, VCTVADEYSGCGDAVAKEACNRA archaeocins, GLC archaea)
AP01194 Ref, Lacticin 3147 CSTNTFSLSDYWGNNGAWCTLTH 2737 (chain A1,
a two- ECMAWCK chain lantibiotic, bacteriocin, bacteria. The
sequence of chain A2 is given in Info; XXD3) AP01195 Ref,
Salivaricin A KRGSGWIATITDDCPNSVFVCC 2738 (SalA, lantibiotic,
bacteriocin, bacteria) AP01196 Ref, Microcin E492
ATYYGNGLYCNKEKCWVDWNQA 2739 (MccE492, class KGEIGKIIVNGWVNHGPWAPRR
IIb microcins, bacteriocin, bacteria; BBM; u- MccE492, siderophore
peptide, BBI, XXG) AP01197 Ref, Hiracin JM79 ATYYGNGLYCNKEKCWVDWNQA
2740 (HirJM79, a Sec- KGEIGKIIVNGWVNHGPWAPRR dependent class II
bacteriocin, bacteria) AP01198 Ref, Thermophilin
LSCDEGMLAVGGLGAVGGPWGA 2741 9 (BlpDst, class IIb AVGVLVGAALYCF
bacteriocin, bacteria. beta- chains: BlpUst, BlpEst, BapFst)
AP01199 Ref, Penocin A KYYGNGVHCGKKTCYVDWGQAT 2742 (PenA, class IIa
ASIGKIIVNGWTQHGPWAHR bacteriocin, bacteria) AP01200 Ref,
Salivaricin B GGGVIQTISHECRMNSWQFLFTCCS 2743 (SalB, lantibotic,
bacteriocin, bacteria) AP01201 Ref, Lacticin 481
KGGSGVIHTISHECNMNSWQFVFT 2744 (lantibiotic, class I CCS
bacteriocin, bacteria) AP01202 Ref, Bacteriocin
KGGSGVIHTISHEVIYNSWNFVFTC 2745 J46 (BacJ46, CS bacteriocin,
bacteria) AP01203 Ref, Nukacin A KKKSGVIPTVSHDCHMNSFQFVFT 2746
(NucA, Nukacin CCS ISK-1, NukISK-1, bacteriocin, bacteria) AP01204
Ref, Streptococcin GKNGVFKTISHECHLNTWAFLATC 2747 A-FF22 CS
(LANTIBIOTIC, class I bacteriocin, bacteria) AP01210 Ref,
Jelleine-I PFKLSLHL 2748 (honeybees, insect, XXA) AP01211 Ref,
Jelleine-II TPFKLSLHL 2749 (honeybees, insect, XXA) AP01212 Ref,
Jelleine-III EPFKLSLHL 2750 (honeybees, insect, XXA) AP01213 Ref,
EFRGSIVIQGTKEGKSRPSLDIDYK 2751 Hymenoptaecin
QRVYDKNGMTGDAYGGLNIRPGQ (honeybees, insect PSRQHAGFEFGKEYKNGFIKGQSE
defensin, XXcooh) VQRGPGGRLSPYFGINGGFRF AP01216 Ref, Ascaphin-1
GFRDVLKGAAKAFVKTVAGHIAN 2752 (frog, XXA) AP01218 Ref, Ascaphin-3
GFRDVLKGAAKAFVKTVAGHIANI 2753 (frog) AP01220 Ref, Ascaphin-5
GIKDWIKGAAKKLIKTVASNIANQ 2754 (frog) AP01222 Ref, Ascaphin-7
GFKDWIKGAAKKLIKTVASSIANQ 2755 (frog) AP01223 Ref, Ascaphin-8
GFKDLLKGAAKALVKTVLF 2756 (frog, XXA) AP01226 Ref, Microcin C7
MRTGNAD 2757 (MccC7, microcin C51, MccC51, class I microcins,
bacteriocins, bacteria. Others: MccA; XXamp; BBPe) AP01227 Ref,
Microcin B17 VGIGGGGGGGGGGSCGGQGGGCG 2758 (MccB17, class I
GCSNGCSGGNGGSGGSGSHI microcins, bacteriocins, Gram- negative
bacteria; BBPe) AP01228 Ref, Microcin V ASGRDIAMAIGTLSGQFVAGGIGA
2759 (MccV, (old name) AAGGVAGGAIYDYASTHKPNPAM Colicin V, ColV;
SPSGLGGTIKQKPEGIPSEAWNYAA class II microcins, GRLCNWSPNNLSDVCL
bacteriocins, Gram- negative bacteria) AP01229 Ref, Microcin L
GDVNWVDVGKTVATNGAGVIGG 2760 (MccL, class IIa
AFGAGLCGPVCAGAFAVGSSAAV microcins, AALYDAAGNSNSAKQKPEGLPPEA
bacteriocins, Gram- WNYAEGRMCNWSPNNLSDVCL negative bacteria)
AP01230 Ref, Microcin M DGNDGQAELIAIGSLAGTFISPGFG 2761 (MccM, class
IIb SIAGAYIGDKVHSWATTATVSPSM microcins, SPSGIGLSSQFGSGRGTSSASSSAGS
bacteriocins, Gram- GS negative bacteria) AP01231 Ref, Microcin H47
GGAPATSANAAGAAAIVGALAGIP 2762 (MccH47, class IIb
GGPLGVVVGAVSAGLTTGIGSTVG microcins, SGSASSSAGGGS bacteriocins,
Gram- negative bacteria) AP01232 Ref, Microcin I47
MNLNGLPASTNVIDLRGKDMGTYI 2763 (MccI47, class IIb
DANGACWAPDTPSIIMYPGGSGPS microcins, YSMSSSTSSANSGS bacteriocins,
Gram- negative bacteria) Aibellin *Ac U A U A U A Q U F U G U U P V
U U E E 2764 [NHC(CH2Ph)HCH2NHCH2CH2]OH Alamethicin_F-30 * Ac U P U
A U A Q U V U G L U P V U U E Q F 2765 OH Alamethicin_F-50 * Ac U P
U A U A Q U V U G L U P V U U Q Q F 2766 OH Alamethicin_II * Ac U P
U A U U Q U V U G L U P V U U E Q F 2767 OH Ampullosporin * Ac W A
U U L U Q U U U Q L U Q L OH 2768 Ampullosporin_B * Ac W A U U L U
Q A U U Q L U Q L OH 2769 Ampullosporin_C * Ac W A U U L U Q U A U
Q L U Q L OH 2770 Ampullosporin_D * Ac W A U U L U Q U U A Q L U Q
L OH 2771 Ampullosporin_E1 * Ac W A U U L U Q A U U Q L A Q L OH
2772 Ampullosporin_E2 * Ac W A U U L U Q U A A Q L U Q L OH 2773
Ampullosporin_E3 * Ac W A U U L U Q U U A Q L A Q L OH 2774
Ampullosporin_E4 * Ac W A U U L U Q A A U Q L U Q L OH 2775
Antiamoebin_I * Ac F U U U J G L U U O Q J O U P F OH 2776
Antiamoebin_II * Ac F U U U J G L U U O Q J P U P F OH 2777
Antiamoebin_III * Ac F U U U U G L U U O Q J O U P F OH 2778
Antiamoebin_IV * Ac F U U U J G L U U O Q J O U P F OH 2779
Antiamoebin_V * Ac F U U U J A L U U O Q J O U P F OH 2780
Antiamoebin_VI * Ac F U U U U G L U U O Q U O U P F OH 2781
Antiamoebin_VII * Ac F A U J U G L U U O Q J O U P F OH 2782
Antiamoebin_VIII * Ac F U U U J G L U U O Q U O U P F OH 2783
Antiamoebin_IX * Ac F U A U J G L U U O Q J O U P F OH 2784
Antiamoebin_X * Ac F U U U J G L J U O Q U O U P F OH 2785
Antiamoebin_XI * Ac F U U U U A L U U O Q J O U P F OH 2786
Antiamoebin_XII * Ac F U U U U G L A U O Q J O U P F OH 2787
Antiamoebin_XIII * Ac V U U U U G L U U O Q J O U P F OH 2788
Antiamoebin_XIV * Ac V U U U V G L U U O Q J O U P F OH 2789
Antiamoebin_XV * Ac L U U U U G L U U O Q J O U P F OH 2790
Antiamoebin_XVI * Ac L U U U J G L U U O Q J O U P F OH 2791
Atroviridin_A * Ac U P U A U A Q U V U G L U P V U U Q Q F 2792 OH
Atroviridin_B * Ac U P U A U A Q U V U G L U P V U J Q Q F 2793 OH
Atroviridin_C * Ac U P U A U U Q U V U G L U P V U J Q Q F 2794 OH
Bergofungin_A * Ac V U U U V G L U U O Q J O U F OH 2795
Bergofungin_B * Ac V U U U V G L V U O Q U O U F OH 2796
Bergofungin_C * Ac V U U U V G L U U O Q U O U F OH 2797
Bergofungin_D * Ac V U U V G L U U O Q U O U F OH 2798 Boletusin *
Ac F U A U J L Q G U U A A U P U U U Q W 2799 OH Cephaibol_A * Ac F
U U U U G L J U O Q J O U P F OH 2800 Cephaibol_A2 * Ac F U U U U A
L J U O Q J O U P F OH 2801 Cephaibol_B * Ac F U U U J G L J U O Q
J O U P F OH 2802 Cephaibol_C * Ac F U U U U G L J U O Q U O U P F
OH 2803 Cephaibol_D * Ac F U U U U G L U U O Q U O U P F OH 2804
Cephaibol_E * Ac F U U U U G L U U O Q J O U P F OH 2805
Cephaibol_P * Ac F J Q U I T U L U O Q U O U P F S OH 2806
Cephaibol_Q * Ac F J Q U I T U L U P Q U O U P F S OH 2807
Cervinin_1 * Ac L U P U L U P A U P V L OH 2808 Cervinin_2 * Ac L U
P U L U P A U P V L OCOCH3 2809 Chrysospermin_A * Ac F U S U U L Q
G U U A A U P U U U Q W 2810 OH Chrysospermin_B * Ac F U S U U L Q
G U U A A U P J U U Q W 2811 OH Chrysospermin_C * Ac F U S U J L Q
G U U A A U P U U U Q W 2812 OH Chrysospermin_D * Ac F U S U J L Q
G U U A A U P J U U Q W 2813 OH Clonostachin * Ac U O L J O L J O U
J U O J I 2814 O[CH(CH(OH)CH2OH)CH(OH)CH(OH)CH2]OH Emerimicin_II_A
* Ac W I Q U I T U L U O Q U O U P F OH 2815 Emerimicin_II_B * Ac W
I Q J I T U L U O Q U O U P F OH 2816 Emerimicin_III * Ac F U U U V
G L U U O Q J O U F OH 2817 Emerimicin_IV * Ac F U U U V G L U U O
Q J O A F OH 2818 Harzianin_HB_I * Ac U N L I U P J L U P L OH 2819
Harzianin_HC_I * Ac U N L U P S V U P U L U P L OH 2820
Harzianin_HC_III * Ac U N L U P S V U P J L U P L OH 2821
Harzianin_HC_IX * Ac U N L U P A I U P J L U P L OH 2822
Harzianin_HC_VI * Ac U N L U P A V U P U L U P L OH 2823
Harzianin_HC_VIII * Ac U N L U P A V U P J L U P L OH 2824
Harzianin_HC_VIII * Ac U N L U P A V U P J L U P L OH 2825
Harzianin_HC_X * Ac U Q L U P A V U P J L U P L OH 2826
Harzianin_HC_XI * Ac U N L U P S I U P U L U P L OH 2827
Harzianin_HC_XII * Ac U N L U P S I U P J L U P L OH 2828
Harzianin_HC_XIII * Ac U Q L U P S I U P J L U P L OH 2829
Harzianin_HC_XIV * Ac U N L U P A I U P U L U P L OH 2830
Harzianin_HC_XV * Ac U Q L U P A I U P J L U P L OH 2831
Harzianin_HK_VI * Ac U N I I U P L L U P L OH 2832 Harzianin_PCU4 *
Ac U N L U P S I U P U L U P V OH 2833 Helioferin_A * Fa P ZZ A U I
I U U AAE 2834 Helioferin_B * Fa P ZZ A U I I U U AMAE 2835
Heptaibin * Ac F U U U V G L U U O Q U O U F OH 2836 Hypelcin_A *
Ac U P U A U U Q L U G U U U P V U U Q Q L 2837 OH Hypelcin_A_I *
Ac U P U A U U Q U L U G U U P V U U Q Q L 2838 OH Hypelcin_A_II *
Ac U P U A U A Q U L U G U U P V U U Q Q L 2839 OH Hypelcin_A_III *
Ac U P U A U U Q U L U G U U P V U U Q Q 2840 [C7H16NO]
Hypelcin_A_IV * Ac U P U A U U Q U I U G U U P V U U Q Q L 2841 OH
Hypelcin_A-III * Ac U P U A U U Q U L U G U U P V U J Q Q L 2842 OH
Hypelcin_A-IX * Ac U P U A U U Q U I U G U U P V U J Q Q L 2843 OH
Hypelcin_A-V * Ac U P U A U U Q U L U G U U P V U U Q Q I 2844 OH
Hypelcin_A-VI * Ac U P U A U A Q U L U G U U P V U U Q Q I 2845 OH
Hypelcin_A-VII * Ac U P U A U A Q U L U G U U P V U J Q Q L 2846 OH
Hypelcin_A-VIII * Ac U P U A U A Q U I U G U U P V U U Q Q L 2847
OH Hypelcin_B_I * Ac U P U A U U Q U L U G U U P V U U E Q L 2848
OH Hypelcin_B_II * Ac U P U A U A Q U L U G U U P V U U E Q L 2849
OH Hypelcin_B_III * Ac U P U A U U Q U L U G U U P V U J E Q L 2850
OH Hypelcin_B_IV * Ac U P U A U U Q U I U G U U P V U U E Q L 2851
OH Hypelcin_B_V * Ac U P U A U U Q U L U G U U P V U U E Q I 2852
OH Hypomurocin_A_I * Ac U Q V V U P L L U P L OH 2853
Hypomurocin_A_II * Ac J Q V V U P L L U P L OH 2854
Hypomurocin_A_III * Ac U Q V L U P L I U P L OH 2855
Hypomurocin_A_IV * Ac U Q I V U P L L U P L OH 2856 Hypomurocin_A_V
* Ac U Q I I U P L L U P L OH 2857 Hypomurocin_A_Va * Ac U Q I L U
P L I U P L OH 2858 Hypomurocin_B_I * Ac U S A L U Q U V U G U U P
L U U Q V OH 2859 Hypomurocin_B_II * Ac U S A L U Q U V U G U U P L
U U Q L OH 2860 Hypomurocin_B_IIIa * Ac U A A L U Q U V U G U U P L
U U Q V OH 2861 Hypomurocin_B_IIIb * Ac U S A L U Q J V U G U U P L
U U Q V OH 2862 Hypomurocin_B_IV * Ac U S A L U Q U V U G J U P L U
U Q V OH 2863 Hypomurocin_B_V * Ac U S A L U Q U V U G J U P L U U
Q L OH 2864 Leul_Zervamicin * Ac L I Q J I T U L U O Q U O U P F OH
2865 Longibrachin_A_I * Ac U A U A U A Q U V U G L U P V U U Q Q F
2866 OH Longibrachin_A_II * Ac U A U A U A Q U V U G L U P V U J Q
Q F 2867 OH Longibrachin_A_III * Ac U A U A U U Q U V U G L U P V U
U Q Q F 2868 OH Longibrachin_A_IV * Ac U A U A U U Q U V U G L U P
V U J Q Q F 2869 OH Longibrachin_B_II * Ac U A U A U A Q U V U G L
U P V U U E Q F 2870 OH Longibrachin_B_III * Ac U A U A U A Q U V U
G L U P V U J E Q F 2871 OH LP237_F5 * Oc U P Y U Q Q U Zor Q A L
OH 2872 LP237_F7 * Ac U P F U Q Q U U Q A L OH 2873 LP237_F8 * Oc U
P F U Q Q U Zor Q A L OH 2874 NA_VII * Ac U A A U J Q U U U S L U
OCH3 2875 Paracelsin_A * Ac U A U A U A Q U V U G U U P V U U Q Q
2876 F OH Paracelsin_B * Ac U A U A U A Q U L U G U U P V U U Q Q F
2877 OH Paracelsin_C * Ac U A U A U U Q U V U G U U P V U U Q Q
2878 F OH Paracelsin_D * Ac U A U A U U Q U L U G U U P V U U Q Q F
2879 OH Paracelsin_E * Ac U A U A U A Q U L U G U A P V U U Q Q F
2880 OH Peptaibolin * Ac L U L U F OH 2881 Peptaivirin_A * Ac F U A
U J L Q G U U A A U P J U U Q W 2882 OH Peptaivirin_B * Ac F U S U
J L Q G U U A A U P J U U Q F OH 2883 Polysporin_A * Ac U P U A U U
Q U V U G V U P V U U Q Q F 2884 OH Polysporin_B * Ac U P U A U U Q
U V U G L U P V U U Q Q F 2885 OH Polysporin_C * Ac U P U A U U Q U
I U G L U P V U U Q Q F 2886 OH Polysporin_D * Ac U P U A U U Q U I
U G L U P V U V Q Q F 2887 OH Pseudokinin_KLIII * Ac U N I I U P L
L U P NH2 2888
Pseudokinin_KLVI * Ac U N I I U P L V hydroxyketopiperazine 2889
Samarosporin_I * Ac F U U U V G L U U O Q J O A F OH 2890
Samarosporin_II * Ac F U U U V G L U U O Q J O U F OH 2891
Saturnisporin_SA_I * Ac U A U A U A Q U L U G U U P V U U Q Q F
2892 OH Saturnisporin_SA_II * Ac U A U A U A Q U L U G U U P V U J
Q Q F 2893 OH Saturnisporin_SA_III * Ac U A U A U U Q U L U G U U P
V U U Q Q F 2894 OH Saturnisporin_SA_IV * Ac U A U A U U Q U L U G
U U P V U J Q Q F 2895 OH Stilbellin_I * Ac F U U U V G L U U O Q J
O A F OH 2896 Stilbellin_II * Ac F U U U V G L U U O Q J O U F OH
2897 Stilboflavin_A_1 * Ac U P U A U A Q U V U G U U P V U U E Q V
2898 OH Stilboflavin_A_2 * Ac U P U A U A Q U L U G U U P V U U E Q
V 2899 OH Stilboflavin_A_3 * Ac U P U A U U Q U V U G U A P V U U E
Q L 2900 OH Stilboflavin_A_4 * Ac U P U A U A Q U L U G U U P V U U
E Q L 2901 OH Stilboflavin_A_5 * Ac U P U A U U Q U L U G U U P V U
U E Q V 2902 OH Stilboflavin_A_6 * Ac U P U A U A Q U L U G U U P V
U U E Q J 2903 OH Stilboflavin_A_7 * Ac U P U A U U Q U L U G U U P
V U U E Q I 2904 OH Stilboflavin_B_1 * Ac U P U A U A Q U V U G U U
P V U U Q Q 2905 V OH Stilboflavin_B_2 * Ac U P U A U A Q U L U G U
U P V U U Q Q V 2906 OH Stilboflavin_B_3 * Ac U P U A U A Q U V U G
U U P V U U Q Q L 2907 OH Stilboflavin_B_4 * Ac U P U A U A Q U L U
G U U P V U U Q Q L 2908 OH Stilboflavin_B_5 * Ac U P U A U U Q U L
U G U U P V U U Q Q V 2909 OH Stilboflavin_B_6 * Ac U P U A U U Q U
V U G U U P V U U Q Q 2910 V OH Stilboflavin_B_7 * Ac U P U A U U Q
U L U G U U P V U U Q Q L 2911 OH Stilboflavin_B_8 * Ac U P U A U U
Q U V U G U U P V U U Q Q L 2912 OH Stilboflavin_B_9 * Ac U P U A U
U Q U L U G U U P V U U Q Q I 2913 OH Stilboflavin_B_10 * Ac U P U
A U U Q U V U G U U P V U U Q Q I 2914 OH Suzukacillin * Ac U A U A
U A Q U U U G L U P V U U Q Q F 2915 OH Trichobrachin_A-I * Ac U N
L L U P L U U P L OH 2916 Trichobrachin_A-II * Ac U N L L U P V L U
P V OH 2917 Trichobrachin_A-III * Ac U N V L U P L L U P V OH 2918
Trichobrachin_A-IV * Ac U N L V U P L L U P V OH 2919
Trichobrachin_B-I * Ac U N L L U P V U V P L OH 2920
Trichobrachin_B-II * Ac U N V L U P L U V P L OH 2921
Trichobrachin_B-III * Ac U N L V U P L U V P L OH 2922
Trichobrachin_B-IV * Ac U N L L U P L U V P V OH 2923
Trichocellin_TC-A-I * Ac U A U A U A Q U L U G U U P V U U Q Q F
2924 OH Trichocellin_TC-A-II * Ac U A U A U A Q U L U G U U P V U J
Q Q F 2925 OH Trichocellin_TC-A-III * Ac U A U A U A Q U I U G U U
P V U U Q Q F 2926 OH Trichocellin_TC-A-IV * Ac U A U A U A Q U I U
G U U P V U J Q Q F 2927 OH Trichocellin_TC-A-V * Ac U A U A U A Q
U L U G L U P V U U Q Q F 2928 OH Trichocellin_TC-A-VI * Ac U A U A
U A Q U L U G L U P V U J Q Q F 2929 OH Trichocellin_TC-A- * Ac U A
U A U A Q U I U G L U P V U U Q Q F 2930 VII OH Trichocellin_TC-A-
* Ac U A U A U A Q U I U G L U P V U J Q Q F 2931 VIII OH
Trichocellin_TC-B-I * Ac U A U A U A Q U L U G U U P V U U E Q F
2932 OH Trichocellin_TC-B-II * Ac U A U A U A Q U L U G U U P V U J
E Q F 2933 OH Trichodecenin_TD_I * (Z)-4-decenoyl G G L U G I L OH
2934 Trichodecenin_TD_II * (Z)-4-decenoyl G G L U G L L OH 2935
Trichogin_A_IV * Oc U G L U G G L U G I L OH 2936 Trichokindin_Ia *
Ac U S A U U Q J L U A U U P L U U Q I OH 2937 Trichokindin_Ib * Ac
U S A U J Q U L U A U U P L U U Q I OH 2938 Trichokindin_IIa * Ac U
S A U U Q U L U A J U P L U U Q I OH 2939 Trichokindin_IIb * Ac U S
A U J Q J L U A U U P L U U Q L OH 2940 Trichokindin_IIIa * Ac U S
A U U Q J L U A J U P L U U Q L OH 2941 Trichokindin_IIIb * Ac U S
A U J Q U L U A J U P L U U Q L OH 2942 Trichokindin_IV * Ac U S A
U J Q J L U A U U P L U U Q I OH 2943 Trichokindin_Va * Ac U S A U
U Q J L U A J U P L U U Q I OH 2944 Trichokindin_Vb * Ac U S A U J
Q U L U A J U P L U U Q I OH 2945 Trichokindin_VI * Ac U S A U J Q
J L U A J U P L U U Q L OH 2946 Trichokindin_VII * Ac U S A U J Q J
L U A J U P L U U Q I OH 2947 Trichokonin_Ia * Ac U A U A U A Q U V
U G L A P V U U Q Q F 2948 OH Trichokonin_Ib * Ac U G U A U A Q U V
U G L U P V U U Q Q F 2949 OH Trichokonin_IIa * Ac U A U A U A Q U
V U G L U P A U U Q Q F 2950 OH Trichokonin_IIb * Ac A A U A U A Q
U V U G L U P V U U Q Q F 2951 OH Trichokonin_IIc * Ac U A A A U A
Q U V U G L U P V U U Q Q F 2952 OH Trichokonin_V * Ac U A U A U Q
U V U G L U P V U U Q Q F 2953 OH Trichokonin_VII * Ac U A U A U A
Q U V U G L U P V U J Q Q F 2954 OH Trichokonin_VIII * Ac U A U A U
U Q U V U G L U P V U U Q Q F 2955 OH Trichokonin_IX * Ac U A U A U
A Q U V U G L U P V U J Q Q F 2956 OH Tricholongin_BI * Ac U G F U
U Q U U U S L U P V U U Q Q L 2957 OH Tricholongin_BII * Ac U G F U
U Q U U U S L U P V U J Q Q L 2958 OH Trichopolyn_I * Fa P ZZ A U U
I A U U AMAE 2959 Trichopolyn_II * Fa P ZZ A U U V A U U AMAE 2960
Trichopolyn_III * Fa P ZZ A U U I A U A AMAE 2961 Trichopolyn_IV *
Fa P ZZ A U U V A U A AMAE 2962 Trichopolyn_V * Fa' P ZZ A U U I A
U U AMAE 2963 Trichorovin_TV_Ia * Ac U N V Lx U P Lx Lx U P V OH
2964 Trichorovin_TV_Ib * Ac U N V V U P Lx Lx U P Lx OH 2965
Trichorovin_TV_IIa * Ac U N V V U P Lx Lx U P Lx OH 2966
Trichorovin_TV_IIb * Ac U N Lx V U P Lx Lx U P V OH 2967
Trichorovin_TV_IIIa * Ac U Q V V U P Lx Lx U P Lx OH 2968
Trichorovin_TV_IIIb * Ac U Q V Lx U P Lx Lx U P V OH 2969
Trichorovin_TV_IVa * Ac U Q V V U P Lx Lx U P Lx OH 2970
Trichorovin_TV_IVb * Ac U Q Lx V U P Lx Lx U P V OH 2971
Trichorovin_TV_IVc * Ac U N V Lx U P Lx Lx U P Lx OH 2972
Trichorovin_TV_IXa * Ac U Q V Lx U P Lx Lx U P Lx OH 2973
Trichorovin_TV_IXb * Ac U Q Lx Lx U P Lx Lx U P V OH 2974
Trichorovin_TV_Va * Ac U N V Lx U P Lx Lx U P Lx OH 2975
Trichorovin_TV_Vb * Ac U N Lx Lx U P Lx Lx U P V OH 2976
Trichorovin_TV_VIa * Ac U N V Lx U P Lx Lx U P Lx OH 2977
Trichorovin_TV_VIb * Ac U N Lx Lx U P Lx Lx U P V OH 2978
Trichorovin_TV_VIIa * Ac U N Lx V U P Lx Lx U P Lx OH 2979
Trichorovin_TV_VIIb * Ac U Q V Lx U P Lx Lx U P V OH 2980
Trichorovin_TV_VIII * Ac U Q V Lx U P Lx Lx U P Lx OH 2981
Trichorovin_TV_Xa * Ac U Q Lx V U P Lx Lx U P Lx OH 2982
Trichorovin_TV_Xb * Ac U N Lx Lx U P Lx Lx U P Lx OH 2983
Trichorovin_TV_XIIa * Ac U N I I U P L L U P I OH 2984
Trichorovin_TV_XIIb * Ac U N Lx Lx U P Lx Lx U P L OH 2985
Trichorovin_TV_XIII * Ac U Q Lx Lx U P Lx Lx U P Lx OH 2986
Trichorovin_TV_XIV * Ac U Q Lx Lx U P Lx Lx U P Lx OH 2987
Trichorozin_I * Ac U N I L U P I L U P V OH 2988 Trichorozin_II *
Ac U Q I L U P I L U P V OH 2989 Trichorozin_III * Ac U N I L U P I
L U P L OH 2990 Trichorozin_IV * Ac U Q I L U P I L U P L OH 2991
Trichorzianine_TA_IIIc * Ac U A A U U Q U U U S L U P V U I Q Q W
2992 OH
Trichorzianine_TB_IIa * Ac U A A U U Q U U U S L U P L U I Q E W
2993 OH Trichorzianine_TB_IIIc * Ac U A A U U Q U U U S L U P V U I
Q E W 2994 OH Trichorzianine_TB_IVb * Ac U A A U J Q U U U S L U P
V U I Q E W 2995 OH Trichorzianine_TB_Vb * Ac U A A U U Q U U U S L
U P L U I Q E F OH 2996 Trichorzianine_TB_VIa * Ac U A A U J Q U U
U S L U P L U I Q E F OH 2997 Trichorzianine_TB_VIb * Ac U A A U U
Q U U U S L U P V U I Q E F 2998 OH Trichorzianine_TB_VII * Ac U A
A U J Q U U U S L U P V U I Q E F OH 2999 Trichorzin_HA_I * Ac U G
A U U Q U V U G L U P L U U Q L OH 3000 Trichorzin_HA_II * Ac U G A
U U Q U V U G L U P L U J Q L OH 3001 Trichorzin_HA_III * Ac U G A
U J Q U V U G L U P L U U Q L OH 3002 Trichorzin_HA_V * Ac U G A U
J Q U V U G L U P L U J Q L OH 3003 Trichorzin_HA_VI * Ac U G A U J
Q J V U G L U P L U J Q L OH 3004 Trichorzin_HA_VII * Ac U G A U J
Q V V U G L U P L U J Q L OH 3005 Trichorzin_MA_I * Ac U S A U U Q
U L U G L U P L U U Q V OH 3006 Trichorzin_MA_II * Ac U S A U J Q U
L U G L U P L U U Q V OH 3007 Trichorzin_MA_III * Ac U S A U J Q J
L U G L U P L U U Q V OH 3008 Trichorzin_PA_II * Ac U S A U J Q U V
U G L U P L U U Q W OH 3009 Trichorzin_PA_IV * Ac U S A U J Q J V U
G L U P L U U Q W OH 3010 Trichorzin_PA_V * Ac U S A J J Q U V U G
L U P L U U Q W OH 3011 Trichorzin_PA_VI * Ac U S A U J Q U V U G L
U P L U U Q F OH 3012 Trichorzin_PA_VII * Ac U S A J J Q U V U G L
U P L U U Q W OH 3013 Trichorzin_PA_VIII * Ac U S A U J Q J V U G L
U P L U U Q F OH 3014 Trichorzin_PA_IX * Ac U S A J J Q U V U G L U
P L U U Q F OH 3015 Trichorzin_PAU4 * Ac U S A U U Q U V U G L U P
L U U Q W OH 3016 Trichosporin_TS-B- * Ac U A G U A U Q U Lx A A Vx
A P V U Vx Q 3017 1a-1 Q F OH Trichosporin_TS-B- * Ac U A G A U U Q
U Lx A A Vx A P V U Vx Q 3018 1a-2 Q F OH Trichosporin_TS-B- * Ac U
A G A U U Q U Lx U G Lx A P V U A Q 3019 1b Q F OH
Trichosporin_TS-B- * Ac U A S A U U Q U Lx U G Lx A P V U U Q Q
3020 1d F OH Trichosporin_TS-B- * Ac U A G A U U Q U Lx U G Lx U P
V U U Q 3021 1e Q F OH Trichosporin_TS-B-1f * Ac U A S A U U Q U Lx
U G Lx U P V U U Q Q 3022 F OH Trichosporin_TS-B- * Ac U A G A U U
Q U Lx U G Lx A P V U U Q 3023 1g Q F OH Trichosporin_TS-B- * Ac U
A G A U U Q U Lx U G Lx U P V U Vx Q 3024 1h Q F OH
Trichosporin_TS-B-Ia * Ac U A S A U U Q U L U G L U P V U U Q Q F
3025 OH Trichosporin_TS-B- * Ac U A A A U U Q U L U G L U P V U U Q
Q F 3026 IIIa OH Trichosporin_TS-B- * Ac U A A A U U Q U I U G L U
P V U A Q Q F 3027 IIIb OH Trichosporin_TS-B- * Ac U A A A A U Q U
I U G L U P V U U Q Q F 3028 IIIc OH Trichosporin_TS-B- * Ac U A A
A U U Q U V U G L U P V U U Q Q F 3029 IIId OH Trichosporin_TS-B- *
Ac U A A A U U Q U L U G L U P V U J Q Q F 3030 IVb OH
Trichosporin_TS-B- * Ac U A U A U U Q U V U G L U P V U U Q Q F
3031 IVc OH Trichosporin_TS-B- * Ac U A A A U U Q U V U G L U P V U
J Q Q F 3032 IVd OH Trichosporin_TS-B-V * Ac U A A A U U Q U I U G
L U P V U U Q Q F 3033 OH Trichosporin_TS-B- * Ac U A U A U U Q U I
U G L U P V U U Q Q F 3034 VIa OH Trichosporin_TS-B- * Ac U A A A U
U Q U I U G L U P V U J Q Q F 3035 VIb OH Trichotoxin_A-40 * Ac U G
U L U E U U U A U U P L U J Q V OH 3036 Trichotoxin_A-40_I * Ac U G
U L U Q U U A A U U P L U U E V OH 3037 Trichotoxin_A-40_II * Ac U
G U L U Q U U U A A U P L U U E V OH 3038 Trichotoxin_A-40_III * Ac
U G U L U Q U U A A U U P L U J E V OH 3039 Trichotoxin_A-40_IV *
Ac U G U L U Q U U U A U U P L U U E V OH 3040 Trichotoxin_A-40_V *
Ac U G U L U Q U U U A U U P L U J E V OH 3041 Trichotoxin_A-40_Va
* Ac U A U L U Q U U U A U U P L U U E V OH 3042 Trichotoxin_A-50_E
* Ac U G U L U Q U U U A A U P L U U Q V OH 3043 Trichotoxin_A-50_F
* Ac U G U L U Q U U A A A U P L U J Q V OH 3044 Trichotoxin_A-50_G
* Ac U G U L U Q U U U A A U P L U J Q V OH 3045 Trichotoxin_A-50_H
* Ac U A U L U Q U U U A A U P L U J Q V OH 3046 Trichotoxin_A-50_I
* Ac U G U L U Q U U U A U U P L U J Q V OH 3047 Trichotoxin_A-50_J
* Ac U A U L U Q U U U A U U P L U J Q V OH 3048 Trichovirin-Ia *
Ac U G A L A Q Vx V U G U U P L U U Q L 3049 OH Trichovirin-Ib * Ac
U G A L U Q A V U G J U P L U U Q L OH 3050 Trichovirin-IIa * Ac U
G A L A Q U V U G J U P L U U Q L OH 3051 Trichovirin-IIb * Ac U G
A L U Q U V U G U U P L U U Q L OH 3052 Trichovirin-IIc * Ac U G A
L U Q Vx V U G U U P L U U Q L 3053 OH Trichovirin-IIIa * Ac U G A
L U Q J V U G U U P L U U Q L OH 3054 Trichovirin-IIIb * Ac U G A L
J Q J U U G U U P L U U Q L OH 3055 Trichovirin-IVa * Ac U G A L J
Q J V U G U U P L U U Q L OH 3056 Trichovirin-IVb * Ac U G A L U Q
U V U G J U P L U U Q L OH 3057 Trichovirin-V * Ac U G A L U Q J V
U G J U P L U U Q L OH 3058 Trichovirin-VIa * Ac U G A L U Q J L U
G J U P L U U Q L OH 3059 Trichovirin-VIb * Ac U G A L J Q J V U G
J U P L U U Q L OH 3060 Trikoningin_KA_V * Ac U G A U I Q U U U S L
U P V U I Q Q L OH 3061 Trikoningin_KB_I * Oc U G V U G G V U G I L
OH 3062 Trikoningin_KB_II * Oc J G V U G G V U G I L OH 3063
Tylopeptin_A * Ac W V U J A Q A U S U A L U Q L OH 3064
Tylopeptin_B * Ac W V U U A Q A U S U A L U Q L OH 3065 XR586 * Ac
W J Q U I T U L U P Q U O J P F G OH 3066 Zervamicin_A-1-16 * Boc W
I A U I V U L U P A U P U P F OCH3 3067 Zervamicin_ZIA * Ac W I E J
V T U L U O Q U O U P F OH 3068 Zervamicin_ZIB * Ac W V E J I T U L
U O Q U O U P F OH 3069 Zervamicin_ZIB' * Ac W I E U I T U L U O Q
U O U P F OH 3070 Zervamicin_ZIC * Ac W I E J I T U L U O Q U O U P
F OH 3071 Zervamicin_ZII-1 * Ac W I Q U V T U L U O Q U O U P F OH
3072 Zervamicin_ZII-2 * Ac W I Q U I T U V U O Q U O U P F OH 3073
Zervamicin_ZII-3 * Ac W V Q U I T U L U O Q U O U P F OH 3074
Zervamicin_ZII-4 * Ac W I Q J V T U L U O Q U O U P F OH 3075
Zervamicin_ZII-5 * Ac W I Q J I T U V U O Q U O U P F OH 3076
Zervamicin_ZIIA * Ac W I Q U I T U L U O Q U O U P F OH 3077
Zervamicin_ZIIB * Ac W I Q J I T U L U O Q U O U P F OH 3078
CAMEL135 GWRLIKKILRVFKGL 3079 (CAM135) Novispirin G2
KNLRIIRKGIHIIKKY* 3080 B-33 FKKFWKWFRRF 3081 B-34 LKRFLKWFKRF 3082
B-35 KLFKRWKHLFR 3083 B-36 RLLKRFKHLFK 3084 B-37 FKTFLKWLHRF 3085
B-38 IKQLLHFFQRF 3086 B-39 KLLQTFKQIFR 3087 B-40 RILKELKNLFK 3088
B-41 LKQFVHFIHRF 3089 B-42 VKTLLHIFQRF 3090 B-43 KLVEQLKEIFR 3091
B-44 RVLQEIKQILK 3092 B-45 VKNLAELVHRF 3093 B-46 ATHLLHALQRF 3094
B-47 KLAENVKEILR 3095 B-48 RALHEAKEALK 3096 B-49 FHYFWHWFHRF 3097
B-50 LYHFLHWFQRF 3098 B-51 YLFQTWQHLFR 3099 B-52 YLLTEFQHLFK 3100
B-53 FKTFLQWLHRF 3101 B-54 IKTLLHFFQRF 3102 B-55 KLLQTFNQIFR 3103
B-56 TILQSLKNIFK 3104
B-57 LKQFVKFIHRF 3105 B-58 VKQLLKIFNRF 3106 B-59 KLVQQLKNIFR 3107
B-60 RVLNQVKQILK 3108 B-61 VKKLAKLVRRF 3109 B-62 AKRLLKVLKRF 3110
B-63 KLAQKVKRVLR 3111 B-64 RALKRIKHVLK 3112 1C-1 RRRRWWW 3113 1C-2
RRWWRRW 3114 1C-3 RRRWWWR 3115 1C-4 RWRWRWR 3116 2C-1 RRRFWWR 3117
2C-2 RRWWRRF* 3118 2C-3 RRRWWWF* 3119 2C-4 RWRWRWF* 3120 3C-1
RRRRWWK 3121 3C-2 RRWWRRK 3122 3C-3 RRRWWWK 3123 3C-4 RWRWRWK 3124
4C-1 RRRKWWK 3125 4C-2 RRWKRRK 3126 4C-3 RRRKWWK 3127 4C-4 RWRKRWK
3128 a-3 LHLLHQLLHLLHQF* 3129 a-4 AQAAHQAAHAAHQF* 3130 a-5
KLKKLLKKLKKLLK 3131 a-6 LKLLKKLLKLLKKF* 3132 a-7 LQLLKQLLKLLKQF*
3133 a-8 AQAAKQAAKAAKQF* 3134 a-9 RWRRWWRHFHHFFH* 3135 a-10
KLKKLLKRWRRWWR 3136 a-11 RWRRLLKKLHHLLH* 3137 a-12 KLKKLLKHLHHLLH*
3138 BD-1 FVF RHK WVW KHR FLF 3139 BD-2 VFI HRH VWV HKH VLF 3140
BD-3 WR WR AR WR WR LR WR F 3141 BD-4 WR IH LR AR LH VK FR F 3142
BD-5 LR IH AR FK VH IR LK F 3143 BD-6 FH IK FR VH LK VR FH F 3144
BD-7 FH VK IH FR LH VK FH F 3145 BD-8 LH IH AH FH VH IH LH F 3146
BD-9 FK IH FR LK VH IR FK F 3147 BD-10 FK AH IR FK LR VK FH F 3148
BD-11 LK AK IK FK VK LK IK F 3149 BD-12 WIW KHK FL HRH FLF 3150
BD-13 VFL HRH VI KHK LVF 3151 BD-14 FL HKH VL RHR IVF 3152 BD-15 VF
KHK IV HRH ILF 3153 BD-16 FLF KH LFL HR IFF 3154 BD-17 LF KH ILI HR
VIF 3155 BD-18 FL HKH LF KHK LF 3156 BD-19 VF RHR FI HRH VF 3157
BD-20 FI HK LV HKH VLF 3158 BD-21 VL RH LF RHR IVF 3159 BD-22 LV HK
LIL RH LLF 3160 BD-23 VF KR VLI HK LIF 3161 BD-24 IV RK FLF RHK VF
3162 BD-25 VL KH VIA HKR LF 3163 BD-26 FI RK FLF KH LF 3164 BD-27
VI RH VWV RK LF 3165 BD-28 FLF RHR F RHR LVF 3166 BD-29 LFL HKH A
KHK FLF 3167 BD-30 F KHK F KHK FIF 3168 BD-31 L RHR L RHR LIF 3169
BD-32 LIL K FLF K FVF 3170 BD-33 VLI R ILV R VIF 3171 BD-34 F RHR F
RHR F 3172 BD-35 L KHK L KHK F 3173 BD-36 F K F KHK LIF 3174 BD-37
L R L RHR VLF 3175 BD-38 F K FLF K FLF 3176 BD-39 L R LFL R WLF
3177 BD-40 F K FLF KHK F 3178 BD-41 L R LFL RHR F 3179 BD-42 F K
FLF K F 3180 BD-43 L R LFL R F 3181 AA-1 HHFFHHFHHFFHHF* 3182 AA-2
FHFFHHFFHFFHHF* 3183 AA-3 KLLK-GAT-FHFFHHFFHFFHHF 3184 AA-4
KLLK-FHFFHHFFHFFHHF 3185 AA-5 FHFFHHFFHFFHHFKLLK 3186 RIP YSPWTNF*
3187 Lariatin A c(Gly-Ser-Gln-Leu-Val-Tyr-Arg-Glu)-Trp-Val- 3188
(anti-mycobacteria) Gly-His-Ser-Asn-Val-Ile-Lys-Pro Lariatin B
c(Gly-Ser-Gln-Leu-Val-Tyr-Arg-Glu)-Trp-Val- 3189
(anti-mycobacteria) Gly-His-Ser-Asn-Val-Ile-Lys-Gly-Pro-Pro
Abreviations: U - Aminoisobutyric Acid (Aib); J - Isovaline (Iva);
O - Hydroxyproline (Hyp); Z - Ethylnorvaline (EtNor); x or xx means
L or I at that position; Ac - optionally acetylated N-term; OH,
OCH3 - optional C-term; Alkane long chains are noted in brackets;
*optionally amidated C-terminus. Where protecting groups are shown,
the gropus are optional. Conversely any of the peptides shown
without protecting groups can, optionally bear one or more
protecting groups. Where peptides are shown circularized, linear
forms are also contemplated. Conversely, where linear peptides are
shown circularlized versions are also contemplated.
[0227] In certain embodiments the antimicrobial peptide consists of
or comprises the amino acid sequence of LL-37 (LLGDFFRK
SKEKIGKEFKRIVQRIKD FLRNL VPRTES, SEQ ID NO:3190) or a variant of
LL-37. LL-37 is a cathelicidin anti-microbial corresponding to
amino acids 134-170 of the human cationic antimicrobial protein 18
(hCAP18). In certain embodiments the antimicrobial peptide consists
of or comprises the amino acid sequence of an LL-37 variant as
described in U.S. Patent Publication No: 2009/0156499 A1).
Illustrative variants comprise or consist of the amino acid
sequence having at least 90%, 95%, or 98% sequence identity with
the amino acid sequence FKRIVQRIKDFLRX.sub.1 (SEQ ID NO:3191),
where X.sub.1 is selected from the group consisting of 0, 1, 2, 3,
4, 5, 6, 7, and 8 amino acids. In certain embodiments illustrative
variants comprise or consist of the amino acid sequence having at
least 90%, 95%, or 98% sequence identity with the amino acid
sequence X.sub.1iRLFDKIRQVIRKFX.sub.2 (SEQ ID NO:3192) where
X.sub.1 is 0, 1, 2, 3, 4, 5, 6, 7, or 8 amino acids and X.sub.2 is
0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 amino
acids.
[0228] In certain embodiments the antimicrobial peptide consists of
or comprises the amino acid sequence of an LL-37 variant shown in
Table 15.
TABLE-US-00015 TABLE 15 LL-37 peptide and variants. SEQ ID Amino
acid sequence ID NO LL-37 LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNL 3193
VPRTES Cys-LL-37 CLLGDFFRKSKEKIGKEFKRIVQRIKDFLRN 3194 LVPRTES
LL-37(17-32) FKRIVQRIKDFLRNLV 3195 Cys-LL-37-Cys
CLLGDFFRKSKEKIGKEFKRIVQRIKDFLRN 3196 LVPRTESC LL-37FK-13
FKRIVQRIKDFLR 3197 LL-37FKR FKRIVQRIKDFLRNLVPRTES 3198 LL-37GKE
GKEFKRIVQRIKDFLRNLVPR 3199 LL-37KRI KRIVQRIKDFLRNLVPRTES 3200
LL-37LLG LLGDFFRKSKEKIGKEFKRIV 3201 LL-37RKS
RKSKEKIGKEFKRIVQRIKDFLRNLVPRTES 3202 LL-37SKE SKEKIGKEFKRIVQRIKDFLR
3203 LL-37-Cys LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNL 3204 VPRTESC A
number of antimicrobial peptides are also disclosed in U.S. Pat.
Nos. 7,271,239, 7,223,840, 7,176,276, 6,809,181, 6,699,689,
6,420,116, 6,358,921, 6,316,594, 6,235,973, 6,183,992, 6,143,498,
6,042,848, 6,040,291, 5,936,063, 5,830,993, 5,428,016, 5,424,396,
5,032,574, 4,623,733, which are incorporated herein by reference
for the disclosure of particular antimicrobial peptides.
[0229] v. Ligands.
[0230] In certain embodiments the effector can comprise one or more
ligands, epitope tags, and/or antibodies. In certain embodiments
preferred ligands and antibodies include those that bind to surface
markers on immune cells. Chimeric moieties utilizing such
antibodies as effector molecules act as bifunctional linkers
establishing an association between the immune cells bearing
binding partner for the ligand or antibody and the target
microorganism(s).
[0231] The terms "epitope tag" or "affinity tag" are used
interchangeably herein, and used refers to a molecule or domain of
a molecule that is specifically recognized by an antibody or other
binding partner. The term also refers to the binding partner
complex as well. Thus, for example, biotin or a biotin/avidin
complex are both regarded as an affinity tag. In addition to
epitopes recognized in epitope/antibody interactions, affinity tags
also comprise "epitopes" recognized by other binding molecules
(e.g. ligands bound by receptors), ligands bound by other ligands
to form heterodimers or homodimers, His.sub.6 bound by Ni-NTA,
biotin bound by avidin, streptavidin, or anti-biotin antibodies,
and the like.
[0232] Epitope tags are well known to those of skill in the art.
Moreover, antibodies specific to a wide variety of epitope tags are
commercially available. These include but are not limited to
antibodies against the DYKDDDDK (SEQ ID NO:3205) epitope, c-myc
antibodies (available from Sigma, St. Louis), the HNK-1
carbohydrate epitope, the HA epitope, the HSV epitope, the
His.sub.4 (SEQ ID NO:3206), His.sub.5 (SEQ ID NO:3207), and
His.sub.6 (SEQ ID NO:3208) epitopes that are recognized by the His
epitope specific antibodies (see, e.g., Qiagen), and the like. In
addition, vectors for epitope tagging proteins are commercially
available. Thus, for example, the pCMV-Tag1 vector is an epitope
tagging vector designed for gene expression in mammalian cells. A
target gene inserted into the pCMV-Tag1 vector can be tagged with
the FLAG.RTM. epitope (N-terminal, C-terminal or internal tagging),
the c-myc epitope (C-terminal) or both the FLAG (N-terminal) and
c-myc (C-terminal) epitopes.
[0233] vi. Lipids and Liposomes.
[0234] In certain embodiments the effectors comprise one or more
microparticles or nanoparticles that can be loaded with an effector
agent (e.g., a pharmaceutical, a label, etc.). In certain
embodiments the microparticles or nanoparticles are lipidic
particles. Lipidic particles are microparticles or nanoparticles
that include at least one lipid component forming a condensed lipid
phase. Typically, a lipidic nanoparticle has preponderance of
lipids in its composition. Various condensed lipid phases include
solid amorphous or true crystalline phases; isomorphic liquid
phases (droplets); and various hydrated mesomorphic oriented lipid
phases such as liquid crystalline and pseudocrystalline bilayer
phases (L-alpha, L-beta, P-beta, Lc), interdigitated bilayer
phases, and nonlamellar phases (see, e.g., The Structure of
Biological Membranes, ed. by P. Yeagle, CRC Press, Bora Raton,
Fla., 1991). Lipidic microparticles include, but are not limited to
a liposome, a lipid-nucleic acid complex, a lipid-drug complex, a
lipid-label complex, a solid lipid particle, a microemulsion
droplet, and the like. Methods of making and using these types of
lipidic microparticles and nanoparticles, as well as attachment of
affinity moieties, e.g., antibodies, to them are known in the art
(see, e.g., U.S. Pat. Nos. 5,077,057; 5,100,591; 5,616,334;
6,406,713; 5,576,016; 6,248,363; Bondi et al. (2003) Drug Delivery
10: 245-250; Pedersen et al., (2006) Eur. J. Pharm. Biopharm. 62:
155-162, 2006 (solid lipid particles); U.S. Pat. Nos. 5,534,502;
6,720,001; Shiokawa et al. (2005) Clin. Cancer Res. 11: 2018-2025
(microemulsions); U.S. Pat. No. 6,071,533 (lipid-nucleic acid
complexes), and the like).
[0235] A liposome is generally defined as a particle comprising one
or more lipid bilayers enclosing an interior, typically an aqueous
interior. Thus, a liposome is often a vesicle formed by a bilayer
lipid membrane. There are many methods for the preparation of
liposomes. Some of them are used to prepare small vesicles
(d<0.05 micrometer), some for larger vesicles (d>0.05
micrometer). Some are used to prepare multilamellar vesicles, some
for unilamellar ones. Methods for liposome preparation are
exhaustively described in several review articles such as Szoka and
Papahadjopoulos (1980) Ann. Rev. Biophys. Bioeng., 9: 467, Deamer
and Uster (1983) Pp. 27-51 In: Liposomes, ed. M. J. Ostro, Marcel
Dekker, New York, and the like.
[0236] In various embodiments the liposomes include a surface
coating of a hydrophilic polymer chain. "Surface-coating" refers to
the coating of any hydrophilic polymer on the surface of liposomes.
The hydrophilic polymer is included in the liposome by including in
the liposome composition one or more vesicle-forming lipids
derivatized with a hydrophilic polymer chain. In certain
embodiments, vesicle-forming lipids with diacyl chains, such as
phospholipids, are preferred. One illustrative phospholipid is
phosphatidylethanolamine (PE), which contains a reactive amino
group convenient for coupling to the activated polymers. One
illustrative PE is distearoyl PE (DSPE). Another example is
non-phospholipid double chain amphiphilic lipids, such as diacyl-
or dialkylglycerols, derivatized with a hydrophilic polymer
chain.
[0237] In certain embodiments a hydrophilic polymer for use in
coupling to a vesicle forming lipid is polyethyleneglycol (PEG),
preferably as a PEG chain having a molecular weight between
1,000-10,000 Daltons, more preferably between 1,000-5,000 Daltons,
most preferably between 2,000-5,000 Daltons. Methoxy or
ethoxy-capped analogues of PEG are also useful hydrophilic
polymers, commercially available in a variety of polymer sizes,
e.g., 120-20,000 Daltons.
[0238] Other hydrophilic polymers that can be suitable include, but
are not limited to polylactic acid, polyglycolic acid,
polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline,
polyhydroxypropyl methacrylamide, polymethacrylamide,
polydimethylacrylamide, and derivatized celluloses, such as
hydroxymethylcellulose or hydroxyethylcellulose.
[0239] Preparation of Lipid-Polymer Conjugates Containing these
Polymers Attached to a suitable lipid, such as PE, have been
described, for example in U.S. Pat. No. 5,395,
[0240] The liposomes can, optionally be prepared for attachment to
one or more targeting moieties described herein. Here the lipid
component included in the liposomes would include either a lipid
derivatized with the targeting moiety, or a lipid having a
polar-head chemical group, e.g., on a linker, that can be
derivatized with the targeting moiety in preformed liposomes,
according to known methods.
[0241] Methods of functionalizing lipids and liposomes with
affinity moieties such as antibodies are well known to those of
skill in the art (see, e.g., DE 3,218,121; Epstein et al. (1985)
Proc. Natl. Acad. Sci., USA, 82:3688 (1985); Hwang et al. (1980)
Proc. Natl. Acad. Sci., USA, 77: 4030; EP 52,322; EP 36,676; EP
88,046; EP 143,949; EP 142,641; Japanese patent application
83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324,
all of which are incorporated herein by reference).
[0242] vii. Agents that Physically Disrupt the Extracellular Matrix
within a Community of Microorganisms
[0243] In certain embodiments, peptides can be coupled to agents
that physically disrupt the extracellular matrix within a community
of microorganisms, for example a biofilm. In certain preferred
embodiments, such an agent could be a bacterial cell-wall degrading
enzyme, for example SAL-2, or any species of glycosidase, alginase,
peptidase, proteinase, lipase, or DNA or RNA degrading enzyme or
compound, for example rhRNase. Disruption of extracellular matrix
of biofilms can result in clearance and therapeutic benefit.
[0244] Peptides can also be attached to antimicrobial proteins,
such as Protein Inhibitor C or Colicin, or fragments thereof, for
example the IIa domain of Colicin, or the heparin-binding domain of
Protein Inhibitor C.
[0245] viii. Polymeric Microparticles and/or Nanoparticles.
[0246] In certain embodiments the effector(s) comprise polymeric
microparticles and/or nanoparticles and/or micelles.
[0247] Microparticle and nanoparticle-based drug delivery systems
have considerable potential for treatment of various
microorganisms. Technological advantages of polymeric
microparticles or nanoparticles used as drug carriers are high
stability, high carrier capacity, feasibility of incorporation of
both hydrophilic and hydrophobic substances, and feasibility of
variable routes of administration, including oral application and
inhalation. Polymeric nanoparticles can also be designed to allow
controlled (sustained) drug release from the matrix. These
properties of nanoparticles enable improvement of drug
bioavailability and reduction of the dosing frequency.
[0248] Polymeric nanoparticles are typically micron or submicron
(<1 .mu.m) colloidal particles. This definition includes
monolithic nanoparticles (nanospheres) in which the drug is
adsorbed, dissolved, or dispersed throughout the matrix and
nanocapsules in which the drug is confined to an aqueous or oily
core surrounded by a shell-like wall. Alternatively, in certain
embodiments, the drug can be covalently attached to the surface or
into the matrix.
[0249] Polymeric microparticles and nanoparticles are typically
made from biocompatible and biodegradable materials such as
polymers, either natural (e.g., gelatin, albumin) or synthetic
(e.g., polylactides, polyalkylcyanoacrylates), or solid lipids. In
the body, the drug loaded in nanoparticles is usually released from
the matrix by diffusion, swelling, erosion, or degradation. One
commonly used material is poly(lactide-co-glycolide) (PLG).
[0250] Methods of fabricating and loading polymeric nanoparticles
or microparticles are well known to those of skill in the art.
Thus, for example, Matsumoto et al. (1999) Intl. J. Pharmaceutics,
185: 93-101 teaches the fabrication of
poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide)
nanoparticles, Chawla et al. (2002) Intl. J. Pharmaceutics 249:
127-138, teaches the fabrication and use of poly(e-caprolactone)
nanoparticles delivery of tamifoxen, and Bodmeier et al. (1988)
Intl. J. Pharmaceutics, 43: 179-186, teaches the preparation of
poly(D,L-lactide) microspheres using a solvent evaporation method.
"Intl. J. Pharmaceutics, 1988, 43, 179-186. Other nanoparticle
formulations are described, for example, by Williams et al. (2003)
J. Controlled Release, 91: 167-172; Leroux et al. (1996) J.
Controlled Release, 39: 339-350; Soppimath et al. (2001) J.
Controlled Release, 70:1-20; Brannon-Peppas (1995) Intl. J.
Pharmaceutics, 116: 1-9; and the like.
[0251] C) Peptide Preparation.
[0252] The peptides described herein can be chemically synthesized
using standard chemical peptide synthesis techniques or,
particularly where the peptide does not comprise "D" amino acid
residues, the peptide can be recombinantly expressed. Where the "D"
polypeptides are recombinantly expressed, a host organism (e.g.
bacteria, plant, fungal cells, etc.) can be cultured in an
environment where one or more of the amino acids is provided to the
organism exclusively in a D form. Recombinantly expressed peptides
in such a system then incorporate those D amino acids.
[0253] In certain embodiments, D amino acids can be incorporated in
recombinantly expressed peptides using modified amino acyl-tRNA
synthetases that recognize D-amino acids.
[0254] In certain embodiments the peptides are chemically
synthesized by any of a number of fluid or solid phase peptide
synthesis techniques known to those of skill in the art. Solid
phase synthesis in which the C-terminal amino acid of the sequence
is attached to an insoluble support followed by sequential addition
of the remaining amino acids in the sequence is a preferred method
for the chemical synthesis of the polypeptides of this invention.
Techniques for solid phase synthesis are well known to those of
skill in the art and are described, for example, by Barany and
Merrifield (1963) Solid-Phase Peptide Synthesis; pp. 3-284 in The
Peptides: Analysis, Synthesis, Biology. Vol. 2: Special Methods in
Peptide Synthesis, Part A.; Merrifield et al. (1963) J. Am. Chem.
Soc., 85: 2149-2156, and Stewart et al. (1984) Solid Phase Peptide
Synthesis, 2nd ed. Pierce Chem. Co., Rockford, Ill.
[0255] In one embodiment, the peptides can be synthesized by the
solid phase peptide synthesis procedure using a benzhyderylamine
resin (Beckman Bioproducts, 0.59 mmol of NH.sub.2/g of resin) as
the solid support. The COOH terminal amino acid (e.g.,
t-butylcarbonyl-Phe) is attached to the solid support through a
4-(oxymethyl)phenacetyl group. This is a more stable linkage than
the conventional benzyl ester linkage, yet the finished peptide can
still be cleaved by hydrogenation. Transfer hydrogenation using
formic acid as the hydrogen donor can be used for this purpose.
[0256] It is noted that in the chemical synthesis of peptides,
particularly peptides comprising D amino acids, the synthesis
usually produces a number of truncated peptides in addition to the
desired full-length product. Thus, the peptides are typically
purified using, e.g., HPLC.
[0257] D-amino acids, beta amino acids, non-natural amino acids,
and the like can be incorporated at one or more positions in the
peptide simply by using the appropriately derivatized amino acid
residue in the chemical synthesis. Modified residues for solid
phase peptide synthesis are commercially available from a number of
suppliers (see, e.g., Advanced Chem Tech, Louisville; Nova Biochem,
San Diego; Sigma, St Louis; Bachem California Inc., Torrance,
etc.). The D-form and/or otherwise modified amino acids can be
completely omitted or incorporated at any position in the peptide
as desired. Thus, for example, in certain embodiments, the peptide
can comprise a single modified acid, while in other embodiments,
the peptide comprises at least two, generally at least three, more
generally at least four, most generally at least five, preferably
at least six, more preferably at least seven or even all modified
amino acids. In certain embodiments, essentially every amino acid
is a D-form amino acid.
[0258] As indicated above, the peptides and/or fusion proteins of
this invention can also be recombinantly expressed. Accordingly, in
certain embodiments, the antimicrobial peptides and/or targeting
moieties, and/or fusion proteins of this invention are synthesized
using recombinant expression systems. Generally this involves
creating a DNA sequence that encodes the desired peptide or fusion
protein, placing the DNA in an expression cassette under the
control of a particular promoter, expressing the peptide or fusion
protein in a host, isolating the expressed peptide or fusion
protein and, if required, renaturing the peptide or fusion
protein.
[0259] DNA encoding the peptide(s) or fusion protein(s) described
herein can be prepared by any suitable method as described above,
including, for example, cloning and restriction of appropriate
sequences or direct chemical synthesis.
[0260] This nucleic acid can be easily ligated into an appropriate
vector containing appropriate expression control sequences (e.g.
promoter, enhancer, etc.), and, optionally, containing one or more
selectable markers (e.g. antibiotic resistance genes).
[0261] The nucleic acid sequences encoding the peptides or fusion
proteins described herein can be expressed in a variety of host
cells, including, but not limited to, E. coli, other bacterial
hosts, yeast, fungus, and various higher eukaryotic cells such as
insect cells (e.g. SF3), the COS, CHO and HeLa cells lines and
myeloma cell lines. The recombinant protein gene will typically be
operably linked to appropriate expression control sequences for
each host. For E. coli this can include a promoter such as the T7,
tip, or lambda promoters, a ribosome binding site and preferably a
transcription termination signal. For eukaryotic cells, the control
sequences can include a promoter and often an enhancer (e.g., an
enhancer derived from immunoglobulin genes, SV40, cytomegalovirus,
etc.), and a polyadenylation sequence, and may include splice donor
and acceptor sequences.
[0262] The plasmids can be transferred into the chosen host cell by
well-known methods such as calcium chloride transformation for E.
coli and calcium phosphate treatment or electroporation for
mammalian cells. Cells transformed by the plasmids can be selected
by resistance to antibiotics conferred by genes contained on the
plasmids, such as the amp, gpt, neo and hyg genes.
[0263] Once expressed, the recombinant peptide(s) or fusion
protein(s) can be purified according to standard procedures of the
art, including ammonium sulfate precipitation, affinity columns,
column chromatography, gel electrophoresis and the like (see,
generally, R. Scopes, (1982) Protein Purification, Springer-Verlag,
N.Y.; Deutscher (1990) Methods in Enzymology Vol. 182: Guide to
Protein Purification., Academic Press, Inc. N.Y.). Substantially
pure compositions of at least about 90 to 95% homogeneity are
preferred, and 98 to 99% or more homogeneity are most
preferred.
[0264] One of skill in the art would recognize that after chemical
synthesis, biological expression, or purification, the peptide(s)
or fusion protein(s) may possess a conformation substantially
different than desired native conformation. In this case, it may be
necessary to denature and reduce the peptide or fusion protein and
then to cause the molecule to re-fold into the preferred
conformation. Methods of reducing and denaturing proteins and
inducing re-folding are well known to those of skill in the art
(see, e.g., Debinski et al. (1993) J. Biol. Chem., 268:
14065-14070; Kreitman and Pastan (1993) Bioconjug. Chem., 4:
581-585; and Buchner, et al., (1992) Anal. Biochem., 205: 263-270).
Debinski et al., for example, describes the denaturation and
reduction of inclusion body proteins in guanidine-DTE. The protein
is then refolded in a redox buffer containing oxidized glutathione
and L-arginine.
[0265] One of skill would recognize that modifications can be made
to the peptide(s) and/or fusion protein(s) proteins without
diminishing their biological activity. Some modifications may be
made to facilitate the cloning, expression, or incorporation of the
targeting molecule into a fusion protein. Such modifications are
well known to those of skill in the art and include, for example, a
methionine added at the amino terminus to provide an initiation
site, or additional amino acids (e.g., poly His) placed on either
terminus to create conveniently located restriction sites or
termination codons or purification sequences.
[0266] D) Joining Targeting Moieties to Effectors.
[0267] i. Chemical Conjugation.
[0268] Chimeric moieties are formed by joining one or more of the
targeting moieties described herein to one or more effectors. In
certain embodiments the targeting moieties are attached directly to
the effector(s) via naturally occurring reactive groups or the
targeting moiety and/or the effector(s) can be functionalized to
provide such reactive groups.
[0269] In various embodiments the targeting moieties are attached
to effector(s) via one or more linking agents. Thus, in various
embodiments the targeting moieties and the effector(s) can be
conjugated via a single linking agent or multiple linking agents.
For example, the targeting moiety and the effector can be
conjugated via a single multifunctional (e.g., bi-, tri-, or
tetra-) linking agent or a pair of complementary linking agents. In
another embodiment, the targeting moiety and the effector are
conjugated via two, three, or more linking agents. Suitable linking
agents include, but are not limited to, e.g., functional groups,
affinity agents, stabilizing groups, and combinations thereof.
[0270] In certain embodiments the linking agent is or comprises a
functional group. Functional groups include monofunctional linkers
comprising a reactive group as well as multifunctional crosslinkers
comprising two or more reactive groups capable of forming a bond
with two or more different functional targets (e.g., labels,
proteins, macromolecules, semiconductor nanocrystals, or
substrate). In some preferred embodiments, the multifunctional
crosslinkers are heterobifunctional crosslinkers comprising two or
more different reactive groups.
[0271] Suitable reactive groups include, but are not limited to
thiol (--SH), carboxylate (COOH), carboxyl (--COOH), carbonyl,
amine (NH.sub.2), hydroxyl (--OH), aldehyde (--CHO), alcohol (ROH),
ketone (R.sub.2CO), active hydrogen, ester, sulfhydryl (SH),
phosphate (--PO.sub.3), or photoreactive moieties. Amine reactive
groups include, but are not limited to e.g., isothiocyanates,
isocyanates, acyl azides, NHS esters, sulfonyl chlorides, aldehydes
and glyoxals, epoxides and oxiranes, carbonates, arylating agents,
imidoesters, carbodiimides, and anhydrides. Thiol-reactive groups
include, but are not limited to e.g., haloacetyl and alkyl halide
derivates, maleimides, aziridines, acryloyl derivatives, arylating
agents, and thiol-disulfides exchange reagents. Carboxylate
reactive groups include, but are not limited to e.g., diazoalkanes
and diazoacetyl compounds, such as carbonyldiimidazoles and
carbodiimides. Hydroxyl reactive groups include, but are not
limited to e.g., epoxides and oxiranes, carbonyldiimidazole,
oxidation with periodate, N,N'-disuccinimidyl carbonate or
N-hydroxylsuccimidyl chloroformate, enzymatic oxidation, alkyl
halogens, and isocyanates. Aldehyde and ketone reactive groups
include, but are not limited to e.g., hydrazine derivatives for
schiff base formation or reduction amination. Active hydrogen
reactive groups include, but are not limited to e.g., diazonium
derivatives for mannich condensation and iodination reactions.
Photoreactive groups include, but are not limited to e.g., aryl
azides and halogenated aryl azides, benzophenones, diazo compounds,
and diazirine derivatives.
[0272] Other suitable reactive groups and classes of reactions
useful in forming chimeric moieties include those that are well
known in the art of bioconjugate chemistry. Currently favored
classes of reactions available with reactive chelates are those
which proceed under relatively mild conditions. These include, but
are not limited to, nucleophilic substitutions (e.g., reactions of
amines and alcohols with acyl halides, active esters),
electrophilic substitutions (e.g., enamine reactions), and
additions to carbon-carbon and carbon-heteroatom multiple bonds
(e.g., Michael reaction, Diels-Alder addition). These and other
useful reactions are discussed in, for example, March (1985)
Advanced Organic Chemistry, 3rd Ed., John Wiley & Sons, New
York, Hermanson (1996) Bioconjugate Techniques, Academic Press, San
Diego; and Feeney et al. (1982) Modification of Proteins; Advances
in Chemistry Series, Vol. 198, American Chemical Society,
Washington, D.C.
[0273] In certain embodiments, the linking agent comprises a
chelator. For example, the chelator comprising the molecule, DOTA
(DOTA=1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane),
can readily be labeled with a radiolabel, such as Gd.sup.3+ and
.sup.64Cu, resulting in Gd.sup.3+-DOTA and .sup.64Cu-DOTA
respectively, attached to the targeting moiety. Other suitable
chelates are known to those of skill in the art, for example,
1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) derivatives
being among the most well known (see, e.g., Lee et al. (1997) Nucl
Med. Biol. 24: 2225-23019).
[0274] A "linker" or "linking agent" as used herein, is a molecule
that is used to join two or more molecules. In certain embodiments
the linker is typically capable of forming covalent bonds to both
molecule(s) (e.g., the targeting moiety and the effector). Suitable
linkers are well known to those of skill in the art and include,
but are not limited to, straight or branched-chain carbon linkers,
heterocyclic carbon linkers, or peptide linkers. In certain
embodiments the linkers can be joined to the constituent amino
acids through their side groups (e.g., through a disulfide linkage
to cysteine). However, in certain embodiments, the linkers will be
joined to the alpha carbon amino and carboxyl groups of the
terminal amino acids.
[0275] A bifunctional linker having one functional group reactive
with a group on one molecule (e.g., a targeting peptide), and
another group reactive on the other molecule (e.g., an
antimicrobial peptide), can be used to form the desired conjugate.
Alternatively, derivatization can be performed to provide
functional groups. Thus, for example, procedures for the generation
of free sulfhydryl groups on peptides are also known (See U.S. Pat.
No. 4,659,839).
[0276] In certain embodiments the linking agent is a
heterobifunctional crosslinker comprising two or more different
reactive groups that form a heterocyclic ring that can interact
with a peptide. For example, a heterobifunctional crosslinker such
as cysteine may comprise an amine reactive group and a
thiol-reactive group can interact with an aldehyde on a derivatized
peptide. Additional combinations of reactive groups suitable for
heterobifunctional crosslinkers include, for example, amine- and
sulfhydryl reactive groups; carbonyl and sulfhydryl reactive
groups; amine and photoreactive groups; sulfhydryl and
photoreactive groups; carbonyl and photoreactive groups;
carboxylate and photoreactive groups; and arginine and
photoreactive groups. In one embodiment, the heterobifunctional
crosslinker is SMCC.
[0277] Many procedures and linker molecules for attachment of
various molecules to peptides or proteins are known (see, e.g.,
European Patent Application No. 188,256; U.S. Pat. Nos. 4,671,958,
4,659,839, 4,414,148, 4,699,784; 4,680,338; 4,569,789; and
4,589,071; and Borlinghaus et al. (1987) Cancer Res. 47:
4071-4075). Illustrative linking protocols are provided herein in
Examples 2 and 3.
[0278] ii. Fusion Proteins.
[0279] In certain embodiments where the targeting moiety and
effector are both peptides or both comprise peptides, the chimeric
moiety can be chemically synthesized or recombinantly expressed as
a fusion protein (i.e., a chimeric fusion protein).
[0280] In certain embodiments the chimeric fusion proteins are
synthesized using recombinant DNA methodology. Generally this
involves creating a DNA sequence that encodes the fusion protein,
placing the DNA in an expression cassette under the control of a
particular promoter, expressing the protein in a host, isolating
the expressed protein and, if required, renaturing the protein.
[0281] DNA encoding the fusion proteins can be prepared by any
suitable method, including, for example, cloning and restriction of
appropriate sequences or direct chemical synthesis by methods such
as the phosphotriester method of Narang et al. (1979) Meth.
Enzymol. 68: 90-99; the phosphodiester method of Brown et al.
(1979) Meth. Enzymol. 68: 109-151; the diethylphosphoramidite
method of Beaucage et al. (1981) Tetra. Lett., 22: 1859-1862; and
the solid support method of U.S. Pat. No. 4,458,066.
[0282] Chemical synthesis produces a single stranded
oligonucleotide. This can be converted into double stranded DNA by
hybridization with a complementary sequence or by polymerization
with a DNA polymerase using the single strand as a template. One of
skill would recognize that while chemical synthesis of DNA is
limited to sequences of about 100 bases, longer sequences can be
obtained by the ligation of shorter sequences.
[0283] Alternatively, subsequences can be cloned and the
appropriate subsequences cleaved using appropriate restriction
enzymes. The fragments can then be ligated to produce the desired
DNA sequence.
[0284] In certain embodiments, DNA encoding fusion proteins of the
present invention may be cloned using DNA amplification methods
such as polymerase chain reaction (PCR). Thus, for example, the
nucleic acid encoding a targeting antibody, a targeting peptide,
and the like is PCR amplified, using a sense primer containing the
restriction site for NdeI and an antisense primer containing the
restriction site for HindIII. This produces a nucleic acid encoding
the targeting sequence and having terminal restriction sites.
Similarly an effector and/or effector/linker/spacer can be provided
having complementary restriction sites. Ligation of sequences and
insertion into a vector produces a vector encoding the fusion
protein.
[0285] While the targeting moieties and effector(s) can be directly
joined together, one of skill will appreciate that they can be
separated by a peptide spacer/linker consisting of one or more
amino acids. Generally the spacer will have no specific biological
activity other than to join the proteins or to preserve some
minimum distance or other spatial relationship between them.
However, the constituent amino acids of the spacer may be selected
to influence some property of the molecule such as the folding, net
charge, or hydrophobicity.
[0286] The nucleic acid sequences encoding the fusion proteins can
be expressed in a variety of host cells, including E. coli, other
bacterial hosts, yeast, and various higher eukaryotic cells such as
the COS, CHO and HeLa cells lines and myeloma cell lines. The
recombinant protein gene will be operably linked to appropriate
expression control sequences for each host. For E. coli this
includes a promoter such as the T7, tip, or lambda promoters, a
ribosome binding site and preferably a transcription termination
signal. For eukaryotic cells, the control sequences will include a
promoter and preferably an enhancer derived from immunoglobulin
genes, SV40, cytomegalovirus, etc., and a polyadenylation sequence,
and may include splice donor and acceptor sequences.
[0287] The plasmids can be transferred into the chosen host cell by
well-known methods such as calcium chloride transformation for E.
coli and calcium phosphate treatment or electroporation for
mammalian cells. Cells transformed by the plasmids can be selected
by resistance to antibiotics conferred by genes contained on the
plasmids, such as the amp, gpt, neo and hyg genes.
[0288] Once expressed, the recombinant fusion proteins can be
purified according to standard procedures of the art, including
ammonium sulfate precipitation, affinity columns, column
chromatography, gel electrophoresis and the like (see, generally,
R. Scopes (1982) Protein Purification, Springer-Verlag, N.Y.;
Deutscher (1990) Methods in Enzymology Vol. 182: Guide to Protein
Purification., Academic Press, Inc. N.Y.). Substantially pure
compositions of at least about 90 to 95% homogeneity are preferred,
and 98 to 99% or more homogeneity are most preferred for
pharmaceutical uses. Once purified, partially or to homogeneity as
desired, the polypeptides may then be used therapeutically.
[0289] One of skill in the art would recognize that after chemical
synthesis, biological expression, or purification, the fusion
protein may possess a conformation substantially different than the
native conformations of the constituent polypeptides. In this case,
it may be necessary to denature and reduce the polypeptide and then
to cause the polypeptide to re-fold into the preferred
conformation. Methods of reducing and denaturing proteins and
inducing re-folding are well known to those of skill in the art
(See, Debinski et al. (1993) J. Biol. Chem., 268: 14065-14070;
Kreitman and Pastan (1993) Bioconjug. Chem., 4: 581-585; and
Buchner, et al. (1992) Anal. Biochem., 205: 263-270).
[0290] One of skill would recognize that modifications can be made
to the fusion proteins without diminishing their biological
activity. Some modifications may be made to facilitate the cloning,
expression, or incorporation of the targeting molecule into a
fusion protein. Such modifications are well known to those of skill
in the art and include, for example, a methionine added at the
amino terminus to provide an initiation site, or additional amino
acids placed on either terminus to create conveniently located
restriction sites or termination codons.
[0291] As indicated above, in various embodiments a peptide
linker/spacer is used to join the one or more targeting moieties to
one or more effector(s). In various embodiments the peptide linker
is relatively short, typically less than about 10 amino acids,
preferably less than about 8 amino acids and more preferably about
3 to about 5 amino acids. Suitable illustrative linkers include,
but are not limited to PSGSP ((SEQ ID NO:3209), ASASA (SEQ ID NO:
3210), or GGG. In certain embodiments longer linkers such as
(GGGGS).sub.3 (SEQ ID NO:3211) can be used. Illustrative peptide
linkers and other linkers are shown in Table 16.
TABLE-US-00016 TABLE 16 Illustrative peptide and non-peptide
linkers. Linker SEQ ID NO: AAA GGG GGGG 3212 SGG GGSGGS 3213 SAT
PYP PSPSP 3214 ASA ASASA 3215 PSPSP 3216 KKKK 3217 RRRR 3218 GGGGS
3219 GGGGS GGGGS 3220 GGGGS GGGGS GGGGS 3221 GGGGS GGGGS GGGGS
GGGGS 3222 GGGGS GGGGS GGGGS GGGGS GGGGS 3223 GGGGS GGGGS GGGGS
GGGGS GGGGS GGGGS 3224 2-nitrobenzene or O-nitrobenzyl Nitropyridyl
disulfide Dioleoylphosphatidylethanolamine (DOPE)
S-acetylmercaptosuccinic acid
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA)
.beta.-glucuronide and .beta.-glucuronide variants
Poly(alkylacrylic acid) Benzene-based linkers (for example:
2,5-Bis(hexyloxy)-1,4-bis[2,5-
bis(hexyloxy)-4-formyl-phenylenevinylene]benzene) and like
molecules Disulfide linkages Poly(amidoamine) or like dendrimers
linking multiple target and killing peptides in one molecule Carbon
nanotubes Hydrazone and hydrazone variant linkers PEG of any chain
length Succinate, formate, acetate butyrate, other like organic
acids Aldols, alcohols, or enols Peroxides alkane or alkene groups
of any chain length One or more porphyrin or dye molecules
containing free amide and carboxylic acid groups One or more DNA or
RNA nucleotides, including polyamine and polycarboxyl-containing
variants Inulin, sucrose, glucose, or other single, di or
polysaccharides Linoleic acid or other polyunsaturated fatty acids
Variants of any of the above linkers containing halogen or thiol
groups (All amino-acid-based linkers could be L, D, combinations of
L and D forms, .beta.-form, and the like)
[0292] E) Multiple Targeting Moieties and/or Effectors.
[0293] As indicated above, in certain embodiments, the chimeric
moieties described herein comprise multiple targeting moieties
attached to a single effector or multiple effectors attached to a
single targeting moiety, or multiple targeting moieties attached to
multiple effectors.
[0294] Where the chimeric construct is a fusion protein this is
easily accomplished by providing multiple domains that are
targeting domains attached to one or more effector domains. FIG. 14
schematically illustrates a few, but not all, configurations. In
various embodiments the multiple targeting domains and/or multiple
effector domains can be attached to each other directly or can be
separated by linkers (e.g., amino acid or peptide linkers as
described above).
[0295] When the chimeric construct is a chemical conjugate linear
or branched configurations (e.g., as illustrated in FIG. 14) are
readily produced by using branched or multifunctional linkers
and/or a plurality of different linkers.
[0296] F) Protecting Groups.
[0297] While the various peptides (e.g., targeting peptides,
antimicrobial peptides, STAMPs) described herein may be shown with
no protecting groups, in certain embodiments they can bear one,
two, three, four, or more protecting groups. In various
embodiments, the protecting groups can be coupled to the C- and/or
N-terminus of the peptide(s) and/or to one or more internal
residues comprising the peptide(s) (e.g., one or more R-groups on
the constituent amino acids can be blocked). Thus, for example, in
certain embodiments, any of the peptides described herein can bear,
e.g., an acetyl group protecting the amino terminus and/or an amide
group protecting the carboxyl terminus. One example of such a
protected peptide is the 1845L6-21 STAMP having the amino acid
sequence KFINGVLSQFVLERKPYPKLFKFLRKHLL* (SEQ ID NO:3225), where the
asterisk indicates an amidated carboxyl terminus. Of course, this
protecting group can be can be eliminated and/or substituted with
another protecting group as described herein.
[0298] Without being bound by a particular theory, it was
discovered that addition of a protecting group, particularly to the
carboxyl and in certain embodiments the amino terminus can improve
the stability and efficacy of the peptide.
[0299] A wide number of protecting groups are suitable for this
purpose. Such groups include, but are not limited to acetyl, amide,
and alkyl groups with acetyl and alkyl groups being particularly
preferred for N-terminal protection and amide groups being
preferred for carboxyl terminal protection. In certain particularly
preferred embodiments, the protecting groups include, but are not
limited to alkyl chains as in fatty acids, propionyl, formyl, and
others. Particularly preferred carboxyl protecting groups include
amides, esters, and ether-forming protecting groups. In one
preferred embodiment, an acetyl group is used to protect the amino
terminus and an amide group is used to protect the carboxyl
terminus. These blocking groups enhance the helix-forming
tendencies of the peptides. Certain particularly preferred blocking
groups include alkyl groups of various lengths, e.g., groups having
the formula: CH.sub.3--(CH.sub.2).sub.n--CO-- where n ranges from
about 1 to about 20, preferably from about 1 to about 16 or 18,
more preferably from about 3 to about 13, and most preferably from
about 3 to about 10.
[0300] In certain embodiments, the protecting groups include, but
are not limited to alkyl chains as in fatty acids, propionyl,
formyl, and others. Particularly preferred carboxyl protecting
groups include amides, esters, and ether-forming protecting groups.
In one embodiment, an acetyl group is used to protect the amino
terminus and/or an amino group is used to protect the carboxyl
terminus (i.e., amidated carboxyl terminus). In certain embodiments
blocking groups include alkyl groups of various lengths, e.g.,
groups having the formula: CH.sub.3--(CH.sub.2).sub.n--CO-- where n
ranges from about 3 to about 20, preferably from about 3 to about
16, more preferably from about 3 to about 13, and most preferably
from about 3 to about 10.
[0301] In certain embodiments, the acid group on the C-terminal can
be blocked with an alcohol, aldehyde or ketone group and/or the
N-terminal residue can have the natural amide group, or be blocked
with an acyl, carboxylic acid, alcohol, aldehyde, or ketone
group.
[0302] Other protecting groups include, but are not limited to
Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoreneacetyl group,
1-fluorenecarboxylic group, 9-fluorenecarboxylic group,
9-fluorenone-1-carboxylic group, benzyloxycarbonyl, xanthyl (Xan),
trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt),
4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr),
Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl
(Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc),
4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO),
benzyl (Bzl), benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys),
1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde),
2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl
(2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Bom),
cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO),
t-Butyl (tBu), Acetyl (Ac), and Trifluoroacetyl (TFA).
[0303] Protecting/blocking groups are well known to those of skill
as are methods of coupling such groups to the appropriate
residue(s) comprising the peptides of this invention (see, e.g.,
Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd
ed., John Wiley & Sons, Inc. Somerset, N.J.). In illustrative
embodiment, for example, acetylation is accomplished during the
synthesis when the peptide is on the resin using acetic anhydride.
Amide protection can be achieved by the selection of a proper resin
for the synthesis. For example, a rink amide resin can be used.
After the completion of the synthesis, the semipermanent protecting
groups on acidic bifunctional amino acids such as Asp and Glu and
basic amino acid Lys, hydroxyl of Tyr are all simultaneously
removed. The peptides released from such a resin using acidic
treatment comes out with the n-terminal protected as acetyl and the
carboxyl protected as NH.sub.2 and with the simultaneous removal of
all of the other protecting groups.
[0304] Where amino acid sequences are disclosed herein, amino acid
sequences comprising, one or more protecting groups, e.g., as
described above (or any other commercially available protecting
groups for amino acids used, e.g., in boc or fmoc peptide
synthesis) are also contemplated.
[0305] G) Peptide Circularization.
[0306] In certain embodiments the peptides described herein (e.g.,
AMPs, compound AMPs, STAMPs, etc.) are circularized/cyclized to
produce cyclic peptides. Cyclic peptides, as contemplated herein,
include head/tail, head/side chain, tail/side chain, and side
chain/side chain cyclized peptides. In addition, peptides
contemplated herein include homodet, containing only peptide bonds,
and heterodet containing in addition disulfide, ester,
thioester-bonds, or other bonds.
[0307] The cyclic peptides can be prepared using virtually any
art-known technique for the preparation of cyclic peptides. For
example, the peptides can be prepared in linear or non-cyclized
form using conventional solution or solid phase peptide syntheses
and cyclized using standard chemistries. Preferably, the chemistry
used to cyclize the peptide will be sufficiently mild so as to
avoid substantially degrading the peptide. Suitable procedures for
synthesizing the peptides described herein as well as suitable
chemistries for cyclizing the peptides are well known in the
art.
[0308] In various embodiments cyclization can be achieved via
direct coupling of the N- and C-terminus to form a peptide (or
other) bond, but can also occur via the amino acid side chains.
Furthermore it can be based on the use of other functional groups,
including but not limited to amino, hydroxy, sulfhydryl, halogen,
sulfonyl, carboxy, and thiocarboxy. These groups can be located at
the amino acid side chains or be attached to their N- or
C-terminus.
[0309] Accordingly, it is to be understood that the chemical
linkage used to covalently cyclize the peptides of the invention
need not be an amide linkage. In many instances it may be desirable
to modify the N- and C-termini of the linear or non-cyclized
peptide so as to provide, for example, reactive groups that may be
cyclized under mild reaction conditions. Such linkages include, by
way of example and not limitation amide, ester, thioester,
CH.sub.2--NH, etc. Techniques and reagents for synthesizing
peptides having modified termini and chemistries suitable for
cyclizing such modified peptides are well-known in the art.
[0310] Alternatively, in instances where the ends of the peptide
are conformationally or otherwise constrained so as to make
cyclization difficult, it may be desirable to attach linkers to the
N- and/or C-termini to facilitate peptide cyclization. Of course,
it will be appreciated that such linkers will bear reactive groups
capable of forming covalent bonds with the termini of the peptide.
Suitable linkers and chemistries are well-known in the art and
include those previously described.
[0311] Cyclic peptides and depsipeptides (heterodetic peptides that
include ester (depside) bonds as part of their backbone) have been
well characterized and show a wide spectrum of biological activity.
The reduction in conformational freedom brought about by
cyclization often results in higher receptor-binding affinities.
Frequently in these cyclic compounds, extra conformational
restrictions are also built in, such as the use of D- and
N-alkylated-amino acids, .alpha.,.beta.-dehydro amino acids or
.alpha.,.alpha.-disubstituted amino acid residues.
[0312] Methods of forming disulfide linkages in peptides are well
known to those of skill in the art (see, e.g., Eichler and Houghten
(1997) Protein Pept. Lett. 4: 157-164).
[0313] Reference may also be made to Marlowe (1993) Biorg. Med.
Chem. Lett. 3: 437-44 who describes peptide cyclization on TFA
resin using trimethylsilyl (TMSE) ester as an orthogonal protecting
group; Pallin and Tam (1995) J. Chem. Soc. Chem. Comm. 2021-2022)
who describe the cyclization of unprotected peptides in aqueous
solution by oxime formation; Algin et al. (1994) Tetrahedron Lett.
35: 9633-9636 who disclose solid-phase synthesis of head-to-tail
cyclic peptides via lysine side-chain anchoring; Kates et al.
(1993) Tetrahedron Lett. 34: 1549-1552 who describe the production
of head-to-tail cyclic peptides by three-dimensional solid phase
strategy; Tumelty et al. (1994) J. Chem. Soc. Chem. Comm.
1067-1068, who describe the synthesis of cyclic peptides from an
immobilized activated intermediate, where activation of the
immobilized peptide is carried out with N-protecting group intact
and subsequent removal leading to cyclization; McMurray et al.
(1994) Peptide Res. 7: 195-206) who disclose head-to-tail
cyclization of peptides attached to insoluble supports by means of
the side chains of aspartic and glutamic acid; Hruby et al. (1994)
Reactive Polymers 22: 231-241) who teach an alternate method for
cyclizing peptides via solid supports; and Schmidt and Langer
(1997) J. Peptide Res. 49: 67-73, who disclose a method for
synthesizing cyclotetrapeptides and cyclopentapeptides.
[0314] These methods of peptide cyclization are illustrative and
non-limiting. Using the teaching provide herein, other cyclization
methods will be available to one of skill in the art.
[0315] H) Identification/Verification of Active Peptides
[0316] The active AMPs, STAMPs and the like can be identified
and/or validated using an in vitro screening assay. Indeed, in many
instances the AMPs and/or STAMPS described herein will be used in
vitro as preservatives, topical antimicrobial treatments, and the
like. Additionally, despite certain apparent limitations of in
vitro susceptibility tests, clinical data indicate that a good
correlation exists between minimal inhibitory concentration (MIC)
test results and in vivo efficacy of antibiotic compounds (see,
e.g., Murray et al. (1994) Antimicrobial Susceptibility Testing,
Poupard et al., eds., Plenum Press, New York; Knudsen et al. (1995)
Antimicrob. Agents Chemother. 39(6): 1253-1258; and the like).
Thus, AMPs useful for treating infections and diseases related
thereto are also conveniently identified by demonstrated in vitro
antimicrobial activity against specified microbial targets, e.g.,
as illustrated in Table 4).
[0317] Typically, the in vitro antimicrobial activity of
antimicrobial agents is tested using standard NCCLS bacterial
inhibition assays, or MIC tests (see, National Committee on
Clinical Laboratory Standards "Performance Standards for
Antimicrobial Susceptibility Testing," NCCLS Document M100-S5 Vol.
14, No. 16, December 1994; "Methods for dilution antimicrobial
susceptibility test for bacteria that grow aerobically-Third
Edition," Approved Standard M7-A3, National Committee for Clinical
Standards, Villanova, Pa.).
[0318] It will be appreciated that other assays as are well known
in the art or that will become apparent to those having skill in
the art upon review of this disclosure may also be used to identify
active AMPs. Such assays include, for example, the assay described
in Lehrer et al. (1988) J. Immunol. Meth., 108: 153 and Steinberg
and Lehrer, "Designer Assays for Antimicrobial Peptides: Disputing
the `One Size Fits All` Theory," In: Antibacterial Peptide
Protocols, Shafer, Ed., Humana Press, N.J. Generally, active
peptides of the invention will exhibit MICs (as measured using the
assays described in the examples) of less than about 100 .mu.M,
preferably less than about 80 or 60 .mu.M, more preferably about 50
.mu.M or less, about 25 .mu.M or less, or about 15 .mu.M or less,
or about 10 .mu.M or less.
IV. Administration and Formulations.
[0319] A) Pharmaceutical Formulations.
[0320] In certain embodiments, the antimicrobial peptides and/or
the chimeric constructs (e.g., targeting moieties attached to
antimicrobial peptide(s), targeting moieties attached to detectable
label(s), etc.) are administered to a mammal in need thereof, to a
cell, to a tissue, to a composition (e.g., a food), etc.). In
various embodiments the compositions can be administered to detect
and/or locate, and/or quantify the presence of particular
microorganisms, microorganism populations, biofilms comprising
particular microorganisms, and the like. In various embodiments the
compositions can be administered to inhibit particular
microorganisms, microorganism populations, biofilms comprising
particular microorganisms, and the like.
[0321] These active agents (antimicrobial peptides and/or chimeric
moieties) can be administered in the "native" form or, if desired,
in the form of salts, esters, amides, prodrugs, derivatives, and
the like, provided the salt, ester, amide, prodrug or derivative is
suitable pharmacologically, i.e., effective in the present
method(s). Salts, esters, amides, prodrugs and other derivatives of
the active agents can be prepared using standard procedures known
to those skilled in the art of synthetic organic chemistry and
described, for example, by March (1992) Advanced Organic Chemistry;
Reactions, Mechanisms and Structure, 4th Ed. N.Y.
Wiley-Interscience.
[0322] Methods of formulating such derivatives are known to those
of skill in the art. For example, the disulfide salts of a number
of delivery agents are described in PCT Publication WO 2000/059863
which is incorporated herein by reference. Similarly, acid salts of
therapeutic peptides, peptoids, or other mimetics, and can be
prepared from the free base using conventional methodology that
typically involves reaction with a suitable acid. Generally, the
base form of the drug is dissolved in a polar organic solvent such
as methanol or ethanol and the acid is added thereto. The resulting
salt either precipitates or can be brought out of solution by
addition of a less polar solvent. Suitable acids for preparing acid
addition salts include, but are not limited to both organic acids,
e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid,
oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,
fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic
acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,
p-toluenesulfonic acid, salicylic acid, and the like, as well as
inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like. An acid
addition salt can be reconverted to the free base by treatment with
a suitable base. Certain particularly preferred acid addition salts
of the active agents herein include halide salts, such as may be
prepared using hydrochloric or hydrobromic acids. Conversely,
preparation of basic salts of the active agents of this invention
are prepared in a similar manner using a pharmaceutically
acceptable base such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
In certain embodiments basic salts include alkali metal salts,
e.g., the sodium salt, and copper salts.
[0323] For the preparation of salt forms of basic drugs, the pKa of
the counterion is preferably at least about 2 pH lower than the pKa
of the drug. Similarly, for the preparation of salt forms of acidic
drugs, the pKa of the counterion is preferably at least about 2 pH
higher than the pKa of the drug. This permists the counterion to
bring the solution's pH to a level lower than the pHmax to reach
the salt plateau, at which the solubility of salt prevails over the
solubility of free acid or base. The generalized rule of difference
in pKa units of the ionizable group in the active pharmaceutical
ingredient (API) and in the acid or base is meant to make the
proton transfer energetically favorable. When the pKa of the API
and counterion are not significantly different, a solid complex may
form but may rapidly disproportionate (i.e., break down into the
individual entities of drug and counterion) in an aqueous
environment.
[0324] Preferably, the counterion is a pharmaceutically acceptable
counterion. Suitable anionic salt forms include, but are not
limited to acetate, benzoate, benzylate, bitartrate, bromide,
carbonate, chloride, citrate, edetate, edisylate, estolate,
fumarate, gluceptate, gluconate, hydrobromide, hydrochloride,
iodide, lactate, lactobionate, malate, maleate, mandelate,
mesylate, methyl bromide, methyl sulfate, mucate, napsylate,
nitrate, pamoate (embonate), phosphate and diphosphate, salicylate
and disalicylate, stearate, succinate, sulfate, tartrate, tosylate,
triethiodide, valerate, and the like, while suitable cationic salt
forms include, but are not limited to aluminum, benzathine,
calcium, ethylene diamine, lysine, magnesium, meglumine, potassium,
procaine, sodium, tromethamine, zinc, and the like.
[0325] In various embodiments preparation of esters typically
involves functionalization of hydroxyl and/or carboxyl groups that
are present within the molecular structure of the active agent. In
certain embodiments, the esters are typically acyl-substituted
derivatives of free alcohol groups, i.e., moieties that are derived
from carboxylic acids of the formula RCOOH where R is alkyl, and
preferably is lower alkyl. Esters can be reconverted to the free
acids, if desired, by using conventional hydrogenolysis or
hydrolysis procedures.
[0326] Amides can also be prepared using techniques known to those
skilled in the art or described in the pertinent literature. For
example, amides may be prepared from esters, using suitable amine
reactants, or they may be prepared from an anhydride or an acid
chloride by reaction with ammonia or a lower alkyl amine.
[0327] In various embodiments, the active agents identified herein
are useful for parenteral, topical, oral, nasal (or otherwise
inhaled), rectal, or local administration, such as by aerosol or
transdermally, for detection and/or quantification, and or
localization, and/or prophylactic and/or therapeutic treatment of
infection (e.g., microbial infection). The compositions can be
administered in a variety of unit dosage forms depending upon the
method of administration. Suitable unit dosage forms, include, but
are not limited to powders, tablets, pills, capsules, lozenges,
suppositories, patches, nasal sprays, injectibles, implantable
sustained-release formulations, lipid complexes, etc.
[0328] The active agents (e.g., antimicrobial peptides and/or
chimeric constructs) described herein can also be combined with a
pharmaceutically acceptable carrier (excipient) to form a
pharmacological composition. In certain embodiments,
pharmaceutically acceptable carriers include those approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in/on animals, and more particularly in/on humans. A
"carrier" refers to, for example, a diluent, adjuvant, excipient,
auxiliary agent or vehicle with which an active agent of the
present invention is administered.
[0329] Pharmaceutically acceptable carriers can contain one or more
physiologically acceptable compound(s) that act, for example, to
stabilize the composition or to increase or decrease the absorption
of the active agent(s). Physiologically acceptable compounds can
include, for example, carbohydrates, such as glucose, sucrose, or
dextrans, antioxidants, such as ascorbic acid or glutathione,
chelating agents, low molecular weight proteins, protection and
uptake enhancers such as lipids, compositions that reduce the
clearance or hydrolysis of the active agents, or excipients or
other stabilizers and/or buffers.
[0330] Other physiologically acceptable compounds, particularly of
use in the preparation of tablets, capsules, gel caps, and the like
include, but are not limited to binders, diluent/fillers,
disentegrants, lubricants, suspending agents, and the like.
[0331] In certain embodiments, to manufacture an oral dosage form
(e.g., a tablet), an excipient (e.g., lactose, sucrose, starch,
mannitol, etc.), an optional disintegrator (e.g. calcium carbonate,
carboxymethylcellulose calcium, sodium starch glycollate,
crospovidone etc.), a binder (e.g. alpha-starch, gum arabic,
microcrystalline cellulose, carboxymethylcellulose,
polyvinylpyrrolidone, hydroxypropylcellulose, cyclodextrin, etc.),
and an optional lubricant (e.g., talc, magnesium stearate,
polyethylene glycol 6000, etc.), for instance, are added to the
active component or components (e.g., active peptide) and the
resulting composition is compressed. Where necessary the compressed
product is coated, e.g., known methods for masking the taste or for
enteric dissolution or sustained release. Suitable coating
materials include, but are not limited to ethyl-cellulose,
hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate
phthalate, hydroxypropylmethylcellulose phthalate, and Eudragit
(Rohm & Haas, Germany; methacrylic-acrylic copolymer).
[0332] Other physiologically acceptable compounds include wetting
agents, emulsifying agents, dispersing agents or preservatives that
are particularly useful for preventing the growth or action of
microorganisms. Various preservatives are well known and include,
for example, phenol and ascorbic acid. One skilled in the art would
appreciate that the choice of pharmaceutically acceptable
carrier(s), including a physiologically acceptable compound
depends, for example, on the route of administration of the active
agent(s) and on the particular physio-chemical characteristics of
the active agent(s).
[0333] In certain embodiments the excipients are sterile and
generally free of undesirable matter. These compositions can be
sterilized by conventional, well-known sterilization techniques.
For various oral dosage form excipients such as tablets and
capsules sterility is not required. The USP/NF standard is usually
sufficient.
[0334] In certain therapeutic applications, the compositions of
this invention are administered, e.g., topically administered or
administered to the oral or nasal cavity, to a patient suffering
from infection or at risk for infection or prophylactically to
prevent dental caries or other pathologies of the teeth or oral
mucosa characterized by microbial infection in an amount sufficient
to prevent and/or cure and/or at least partially prevent or arrest
the disease and/or its complications. An amount adequate to
accomplish this is defined as a "therapeutically effective dose."
Amounts effective for this use will depend upon the severity of the
disease and the general state of the patient's health. Single or
multiple administrations of the compositions may be administered
depending on the dosage and frequency as required and tolerated by
the patient. In any event, the composition should provide a
sufficient quantity of the active agents of the formulations of
this invention to effectively treat (ameliorate one or more
symptoms in) the patient.
[0335] The concentration of active agent(s) can vary widely, and
will be selected primarily based on activity of the active
ingredient(s), body weight and the like in accordance with the
particular mode of administration selected and the patient's needs.
Concentrations, however, will typically be selected to provide
dosages ranging from about 0.1 or 1 mg/kg/day to about 50 mg/kg/day
and sometimes higher. Typical dosages range from about 3 mg/kg/day
to about 3.5 mg/kg/day, preferably from about 3.5 mg/kg/day to
about 7.2 mg/kg/day, more preferably from about 7.2 mg/kg/day to
about 11.0 mg/kg/day, and most preferably from about 11.0 mg/kg/day
to about 15.0 mg/kg/day. In certain preferred embodiments, dosages
range from about 10 mg/kg/day to about 50 mg/kg/day. In certain
embodiments, dosages range from about 20 mg to about 50 mg given
orally twice daily. It will be appreciated that such dosages may be
varied to optimize a therapeutic and/or phophylactic regimen in a
particular subject or group of subjects.
[0336] In certain embodiments, the active agents of this invention
are administered to the oral cavity. This is readily accomplished
by the use of lozenges, aersol sprays, mouthwash, coated swabs, and
the like.
[0337] In certain embodiments, the active agent(s) of this
invention are administered topically, e.g., to the skin surface, to
a topical lesion or wound, to a surgical site, and the like.
[0338] In certain embodiments the active agents of this invention
are administered systemically (e.g., orally, or as an injectable)
in accordance with standard methods well known to those of skill in
the art. In other preferred embodiments, the agents, can also be
delivered through the skin using conventional transdermal drug
delivery systems, i.e., transdermal "patches" wherein the active
agent(s) are typically contained within a laminated structure that
serves as a drug delivery device to be affixed to the skin. In such
a structure, the drug composition is typically contained in a
layer, or "reservoir," underlying an upper backing layer. It will
be appreciated that the term "reservoir" in this context refers to
a quantity of "active ingredient(s)" that is ultimately available
for delivery to the surface of the skin. Thus, for example, the
"reservoir" may include the active ingredient(s) in an adhesive on
a backing layer of the patch, or in any of a variety of different
matrix formulations known to those of skill in the art. The patch
may contain a single reservoir, or it may contain multiple
reservoirs.
[0339] In one embodiment, the reservoir comprises a polymeric
matrix of a pharmaceutically acceptable contact adhesive material
that serves to affix the system to the skin during drug delivery.
Examples of suitable skin contact adhesive materials include, but
are not limited to, polyethylenes, polysiloxanes, polyisobutylenes,
polyacrylates, polyurethanes, and the like. Alternatively, the
drug-containing reservoir and skin contact adhesive are present as
separate and distinct layers, with the adhesive underlying the
reservoir which, in this case, may be either a polymeric matrix as
described above, or it may be a liquid or hydrogel reservoir, or
may take some other form. The backing layer in these laminates,
which serves as the upper surface of the device, preferably
functions as a primary structural element of the "patch" and
provides the device with much of its flexibility. The material
selected for the backing layer is preferably substantially
impermeable to the active agent(s) and any other materials that are
present.
[0340] Other formulations for topical delivery include, but are not
limited to, ointments, gels, sprays, fluids, and creams. Ointments
are semisolid preparations that are typically based on petrolatum
or other petroleum derivatives. Creams containing the selected
active agent are typically viscous liquid or semisolid emulsions,
often either oil-in-water or water-in-oil. Cream bases are
typically water-washable, and contain an oil phase, an emulsifier
and an aqueous phase. The oil phase, also sometimes called the
"internal" phase, is generally comprised of petrolatum and a fatty
alcohol such as cetyl or stearyl alcohol; the aqueous phase
usually, although not necessarily, exceeds the oil phase in volume,
and generally contains a humectant. The emulsifier in a cream
formulation is generally a nonionic, anionic, cationic or
amphoteric surfactant. The specific ointment or cream base to be
used, as will be appreciated by those skilled in the art, is one
that will provide for optimum drug delivery. As with other carriers
or vehicles, an ointment base should be inert, stable,
nonirritating and nonsensitizing.
[0341] As indicated above, various buccal, and sublingual
formulations are also contemplated.
[0342] In certain embodiments, one or more active agents of the
present invention can be provided as a "concentrate", e.g., in a
storage container (e.g., in a premeasured volume) ready for
dilution, or in a soluble capsule ready for addition to a volume of
water, alcohol, hydrogen peroxide, or other diluent.
[0343] While the invention is described with respect to use in
humans, it is also suitable for animal, e.g., veterinary use. Thus
certain preferred organisms include, but are not limited to humans,
non-human primates, canines, equines, felines, porcines, ungulates,
largomorphs, and the like.
[0344] B) Nanoemulsion Formulations.
[0345] In certain embodiments the targeting peptides, antimicrobial
peptides and/or chimeric moieties (e.g., STAMPs) as described
herein are formulated in a nanoemulsion. Nanoemulsions include, but
are not limited to oil in water (0/W) nanoemulsions, and water in
oil (W/O) nanoemulsions. Nanoemulsions can be defined as emulsions
with mean droplet diameters ranging from about 20 to about 1000 nm.
Usually, the average droplet size is between about 20 nm or 50 nm
and about 500 nm. The terms sub-micron emulsion (SME) and
mini-emulsion are used as synonyms.
[0346] Illustrative oil in water (O/W) nanoemulsions include, but
are not limited to:
[0347] Surfactant micelles--micelles composed of small molecules
surfactants or detergents (e.g., SDS/PBS/2-propanol) which are
suitable for predominantly hydrophobic peptides.
[0348] Polymer micelles--micelles composed of polymer, copolymer,
or block copolymer surfactants (e.g., Pluronic L64/PBS/2-propanol)
which are suitable for predominantly hydrophobic peptides;
[0349] Blended micelles: micelles in which there is more than one
surfactant component or in which one of the liquid phases
(generally an alcohol or fatty acid compound) participates in the
formation of the micelle (e.g., Octanoic acid/PBS/EtOH) which are
suitable for predominantly hydrophobic peptides;
[0350] Integral peptide micelles--blended micelles in which the
peptide serves as an auxiliary surfactant, forming an integral part
of the micelle (e.g., amphipathic peptide/PBS/mineral oil) which
are suitable for amphipathic peptides; and
[0351] Pickering (solid phase) emulsions--emulsions in which the
peptides are associated with the exterior of a solid nanoparticle
(e.g., polystyrene nanoparticles/PBS/no oil phase) which are
suitable for amphipathic peptides.
[0352] Illustrative water in oil (W/O) nanoemulsions include, but
are not limited to:
[0353] Surfactant micelles--micelles composed of small molecules
surfactants or detergents (e.g., dioctyl
sulfosuccinate/PBS/2-propanol, Isopropylmyristate/PBS/2-propanol,
etc.) which are suitable for predominantly hydrophilic
peptides;
[0354] Polymer micelles--micelles composed of polymer, copolymer,
or block copolymer surfactants (e.g., PLURONIC.RTM.
L121/PBS/2-propanol), which are suitable for predominantly
hydrophilic peptides;
[0355] Blended micelles--micelles in which there is more than one
surfactant component or in which one of the liquid phases
(generally an alcohol or fatty acid compound) participates in the
formation of the micelle (e.g., capric/caprylic
diglyceride/PBS/EtOH) which are suitable for predominantly
hydrophilic peptides;
[0356] Integral peptide micelles--blended micelles in which the
peptide serves as an auxiliary surfactant, forming an integral part
of the micelle (e.g., amphipathic peptide/PBS/polypropylene glycol)
which are suitable for amphipathic peptides; and
[0357] Pickering (solid phase) emulsions--emulsions in which the
peptides are associated with the exterior of a solid nanoparticle
(e.g., chitosan nanoparticles/no aqueous phase/mineral oil) which
are suitable for amphipathic peptides.
[0358] As indicated above, in certain embodiments the nanoemulsions
comprise one or more surfactants or detergents. In some embodiments
the surfactant is a non-anionic detergent (e.g., a polysorbate
surfactant, a polyoxyethylene ether, etc.). Surfactants that find
use in the present invention include, but are not limited to
surfactants such as the TWEEN.RTM., TRITON.RTM., and TYLOXAPOL.RTM.
families of compounds.
[0359] In certain embodiments the emulsions further comprise one or
more cationic halogen containing compounds, including but not
limited to, cetylpyridinium chloride. In still further embodiments,
the compositions further comprise one or more compounds that
increase the interaction ("interaction enhancers") of the
composition with microorganisms (e.g., chelating agents like
ethylenediaminetetraacetic acid, or
ethylenebis(oxyethylenenitrilo)tetraacetic acid in a buffer).
[0360] In some embodiments, the nanoemulsion further comprises an
emulsifying agent to aid in the formation of the emulsion.
Emulsifying agents include compounds that aggregate at the
oil/water interface to form a kind of continuous membrane that
prevents direct contact between two adjacent droplets. Certain
embodiments of the present invention feature oil-in-water emulsion
compositions that may readily be diluted with water to a desired
concentration without impairing their anti-pathogenic
properties.
[0361] In addition to discrete oil droplets dispersed in an aqueous
phase, certain oil-in-water emulsions can also contain other lipid
structures, such as small lipid vesicles (e.g., lipid spheres that
often consist of several substantially concentric lipid bilayers
separated from each other by layers of aqueous phase), micelles
(e.g., amphiphilic molecules in small clusters of 50-200 molecules
arranged so that the polar head groups face outward toward the
aqueous phase and the apolar tails are sequestered inward away from
the aqueous phase), or lamellar phases (lipid dispersions in which
each particle consists of parallel amphiphilic bilayers separated
by thin films of water).
[0362] These lipid structures are formed as a result of hydrophobic
forces that drive apolar residues (e.g., long hydrocarbon chains)
away from water. The above lipid preparations can generally be
described as surfactant lipid preparations (SLPs). SLPs are
minimally toxic to mucous membranes and are believed to be
metabolized within the small intestine (see e.g., Hamouda et al.,
(1998) J. Infect. Disease 180: 1939).
[0363] In certain embodiments the emulsion comprises a
discontinuous oil phase distributed in an aqueous phase, a first
component comprising an alcohol and/or glycerol, and a second
component comprising a surfactant or a halogen-containing compound.
The aqueous phase can comprise any type of aqueous phase including,
but not limited to, water (e.g., dionized water, distilled water,
tap water) and solutions (e.g., phosphate buffered saline solution,
or other buffer systems). The oil phase can comprise any type of
oil including, but not limited to, plant oils (e.g., soybean oil,
avocado oil, flaxseed oil, coconut oil, cottonseed oil, squalene
oil, olive oil, canola oil, corn oil, rapeseed oil, safflower oil,
and sunflower oil), animal oils (e.g., fish oil), flavor oil, water
insoluble vitamins, mineral oil, and motor oil. In certain
embodiments, the oil phase comprises 30-90 vol % of the
oil-in-water emulsion (i.e., constitutes 30-90% of the total volume
of the final emulsion), more preferably 50-80%.
[0364] In certain embodiments the alcohol, when present, is
ethanol.
[0365] While the present invention is not limited by the nature of
the surfactant, in some preferred embodiments, the surfactant is a
polysorbate surfactant (e.g., TWEEN 20.RTM., TWEEN 40.RTM., TWEEN
60.RTM., and TWEEN 80.RTM.), a phenoxypolyethoxyethanol (e.g.,
TRITON.RTM. X-100, X-301, X-165, X-102, and X-200, and
TYLOXAPOL.RTM.), or sodium dodecyl sulfate, and the like.
[0366] In certain embodiments a halogen-containing component is
present. the nature of the halogen-containing compound, in some
preferred embodiments the halogen-containing compound comprises a
chloride salt (e.g., NaCl, KCl, etc.), a cetylpyridinium halide, a
cetyltrimethylammonium halide, a cetyldimethylethylammonium halide,
a cetyldimethylbenzylammonium halide, a cetyltributylphosphonium
halide, dodecyltrimethylammonium halides,
tetradecyltrimethylammonium halides, cetylpyridinium chloride,
cetyltrimethylammonium chloride, cetylbenzyldimethylammonium
chloride, cetylpyridinium bromide, cetyltrimethylammonium bromide,
cetyldimethylethylammonium bromide, cetyltributylphosphonium
bromide, dodecyltrimethylammonium bromide,
tetradecyltrimethylammonium bromide, and the like
[0367] In certain embodiments the emulsion comprises a quaternary
ammonium compound. Quaternary ammonium compounds include, but are
not limited to, N-alkyldimethyl benzyl ammonium saccharinate,
1,3,5-Triazine-1,3,5(2H,4H,6H)-triethanol; 1-Decanaminium,
N-decyl-N,N-dimethyl-, chloride (or) Didecyl dimethyl ammonium
chloride; 2-(2-(p-(Diisobuyl)cresosxy)ethoxy)ethyl dimethyl benzyl
ammonium chloride; 2-(2-(p-(Diisobutyl)phenoxy)ethoxy)ethyl
dimethyl benzyl ammonium chloride; alkyl 1 or
3-benzyl-1-(2-hydroxyethyl)-2-imidazolinium chloride; alkyl
bis(2-hydroxyethyl)benzyl ammonium chloride; alkyl demethyl benzyl
ammonium chloride; alkyl dimethyl 3,4-dichlorobenzyl ammonium
chloride (100% C12); alkyl dimethyl 3,4-dichlorobenzyl ammonium
chloride (50% C14, 40% C12, 10% C16); alkyl dimethyl
3,4-dichlorobenzyl ammonium chloride (55% C14, 23% C12, 20% C16);
alkyl dimethyl benzyl ammonium chloride; alkyl dimethyl benzyl
ammonium chloride (100% C14); alkyl dimethyl benzyl ammonium
chloride (100% C16); alkyl dimethyl benzyl ammonium chloride (41%
C14, 28% C12); alkyl dimethyl benzyl ammonium chloride (47% C12,
18% C14); alkyl dimethyl benzyl ammonium chloride (55% C16, 20%
C14); alkyl dimethyl benzyl ammonium chloride (58% C14, 28% C16);
alkyl dimethyl benzyl ammonium chloride (60% C14, 25% C12); alkyl
dimethyl benzyl ammonium chloride (61% C11, 23% C14); alkyl
dimethyl benzyl ammonium chloride (61% C12, 23% C14); alkyl
dimethyl benzyl ammonium chloride (65% C12, 25% C14); alkyl
dimethyl benzyl ammonium chloride (67% C12, 24% C14); alkyl
dimethyl benzyl ammonium chloride (67% C12, 25% C14); alkyl
dimethyl benzyl ammonium chloride (90% C14, 5% C12); alkyl dimethyl
benzyl ammonium chloride (93% C14, 4% C12); alkyl dimethyl benzyl
ammonium chloride (95% C16, 5% C18); alkyl dimethyl benzyl ammonium
chloride (and) didecyl dimethyl ammonium chloride; alkyl dimethyl
benzyl ammonium chloride (as in fatty acids); alkyl dimethyl benzyl
ammonium chloride (C12-C16); alkyl dimethyl benzyl ammonium
chloride (C12-C18); alkyl dimethyl benzyl and dialkyl dimethyl
ammonium chloride; alkyl dimethyl dimethylbenzyl ammonium chloride;
alkyl dimethyl ethyl ammonium bromide (90% C14, 5% C16, 5% C12);
alkyl dimethyl ethyl ammonium bromide (mixed alkyl and alkenyl
groups as in the fatty acids of soybean oil); alkyl dimethyl
ethylbenzyl ammonium chloride; alkyl dimethyl ethylbenzyl ammonium
chloride (60% C14); alkyl dimethyl isopropylbenzyl ammonium
chloride (50% C12, 30% C14, 17% C16, 3% C18); alkyl trimethyl
ammonium chloride (58% C18, 40% C16, 1% C14, 1% C12); alkyl
trimethyl ammonium chloride (90% C18, 10% C16);
alkyldimethyl(ethylbenzyl)ammonium chloride (C12-18);
Di-(C8-10)-alkyl dimethyl ammonium chlorides; dialkyl dimethyl
ammonium chloride; dialkyl dimethyl ammonium chloride; dialkyl
dimethyl ammonium chloride; dialkyl methyl benzyl ammonium
chloride; didecyl dimethyl ammonium chloride; diisodecyl dimethyl
ammonium chloride; dioctyl dimethyl ammonium chloride; dodecyl
bis(2-hydroxyethyl)octyl hydrogen ammonium chloride; dodecyl
dimethyl benzyl ammonium chloride; dodecylcarbamoyl methyl dimethyl
benzyl ammonium chloride; heptadecyl hydroxyethylimidazolinium
chloride; hexahydro-1,3,5-thris(2-hydroxyethyl)-s-triazine;
myristalkonium chloride (and) Quat RNIUM 14;
N,N-Dimethyl-2-hydroxypropylammonium chloride polymer; n-alkyl
dimethyl benzyl ammonium chloride; n-alkyl dimethyl ethylbenzyl
ammonium chloride; n-tetradecyl dimethyl benzyl ammonium chloride
monohydrate; octyl decyl dimethyl ammonium chloride; octyl dodecyl
dimethyl ammonium chloride; octyphenoxyethoxyethyl dimethyl benzyl
ammonium chloride; oxydiethylenebis (alkyl dimethyl ammonium
chloride); quaternary ammonium compounds, dicoco alkyldimethyl,
chloride; trimethoxysilyl propyl dimethyl octadecyl ammonium
chloride; trimethoxysilyl quats, trimethyl dodecylbenzyl ammonium
chloride; n-dodecyl dimethyl ethylbenzyl ammonium chloride;
n-hexadecyl dimethyl benzyl ammonium chloride; n-tetradecyl
dimethyl benzyl ammonium chloride; n-tetradecyl dimethyl
ethylbenzyl ammonium chloride; and n-octadecyl dimethyl benzyl
ammonium chloride.
[0368] Nanoemulsion formulations and methods of making such are
well known to those of skill in the art and described for example
in U.S. Pat. Nos. 7,476,393, 7,468,402, 7,314,624, 6,998,426,
6,902,737, 6,689,371, 6,541,018, 6,464,990, 6,461,625, 6,419,946,
6,413,527, 6,375,960, 6,335,022, 6,274,150, 6,120,778, 6,039,936,
5,925,341, 5,753,241, 5,698,219, and 5,152,923 and in Fanun et al.
(2009) Microemulsions: Properties and Applications (Surfactant
Science), CRC Press, Boca Ratan Fla.
[0369] C) Formulations Optimizing Activity.
[0370] In certain embodiments, formulations are selected to
optimize binding specificity, and/or binding avidity, and/or
antimicrobial activity, and/or stability/conformation of the
targeting peptide, antimicrobial peptide, chimeric moiety, and/or
STAMP. In this regard, it was a surprising discovery that the
activity of certain STAMPs, and presumably the constituent
targeting peptides and/or antimicrobial peptides was optimized in
the presence of a salt. Accordingly, certain embodiments are
contemplated where the targeting peptide and/or antimicrobial
peptide, and/or STAMP is formulated in combination with one or more
salts. The formulations disclosed herein, however, are not limited
to those containing salt(s). Embodiments, are also contemplated
where the targeting peptide and/or antimicrobial peptide, and/or
STAMP is formulated without the presence of a salt.
[0371] In certain embodiments, sodium chloride plus a little
potassium chloride resulted in the best activity of the salts
tested. However, other salts, e.g., CaCl.sub.2, MgCl.sub.2,
MnCl.sub.2 also enhanced activity. Accordingly, in certain
embodiments, it is contemplated that the targeting peptide(s),
and/or antimicrobial peptide(s), and/or chimeric moieties, and/or
STAMPs are formulated with one or more salts.
[0372] In certain embodiments suitable salts include any of a
number of pharmaceutically acceptable salts. Representative salts
include the hydrobromide, hydrochloride, sulfate, bisulfate,
phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate,
laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate,
fumarate, succinate, tartrate, naphthylate, mesylate, besylate,
glucoheptonate, lactobionate, and laurylsulphonate salts and the
like (see, e.g., Berge et al. (1977) J. Pharm. Sci. 66: 1-19),
although it is noted that citrate salts appear to inhibit the
activity of certain STAMPs.
[0373] In certain embodiments pharmaceutically acceptable salts of
the present invention include the conventional nontoxic salts or
quaternary ammonium salts of the compounds, e.g., from non-toxic
organic or inorganic acids. For example, such conventional nontoxic
salts include those derived from inorganic acids such as
hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric,
and the like; and the salts prepared from organic acids such as
acetic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicyclic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
benzenesulfonic, ethane disulfonic, oxalic, isothionic, and the
like.
[0374] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately treating the compound in
its free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically-acceptable metal
cation, with ammonia, or with a pharmaceutically-acceptable organic
primary, secondary or tertiary amine. Representative alkali or
alkaline earth salts include the lithium, sodium, potassium,
calcium, magnesium, and aluminum salts and the like. Representative
organic amines useful for the formation of base addition salts
include ethylamine, diethylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine and the like (see, for example, Berge et
al., supra; and Stahl and Wermuth (2002) Handbook of Pharmaceutical
Salts: Properties, Selection, and Use, Wiley-VCH, Zurich,
Switzerland).
[0375] In various embodiments, the salt is simply a sodium chloride
and/or a potassium chloride and can readily be prepared, for
example, as a phosphate buffered saline (PBS) solution. In certain
embodiments, the salt concentration is comparable to that found in
0.5.times.PBS to about 2.5.times.PBS, more preferably from about
0.5.times.PBS to about 1.5.times.PBS. In certain embodiments
optimum activity has been observed in 1.times.PBS.
[0376] In various embodiments, the pH of the formulation ranges
from about pH 5.0 to about pH 8.5, preferably from about pH 6.0 to
about pH 8.0, more preferably from about pH 7.0 to about pH 8.0. In
certain embodiments the pH is about pH 7.4.
[0377] While optimum results have been observed for certain STAMPs
using a PBS buffer system, other buffer systems are also
acceptable. Such buffers include, but are not limited to sulfate
buffers, carbonate buffers, Tris buffers, CHAPS buffers, PIPES
buffers, and the like, as long as the salt is included.
[0378] In various embodiments, the targeting peptide, and/or
antimicrobial peptide, and/or chimeric moiety, and/or STAMP is
present in the formulation at a concentration ranging from about 1
nM, to about 1, 10, or 100 mM, more preferably from about 1 nM,
about 10 nM, about 100 nM, about 1 .mu.M, or about 10 .mu.M to
about 50 .mu.M, about 100 .mu.M, about 200 .mu.m, about 300 .mu.M,
about 400 .mu.M, or about 500 .mu.M, preferably from about 1 .mu.M,
about 10 .mu.M, about 25 .mu.M, or about 50 .mu.M to about 1 mM,
about 10 mM, about 20 mM, or about 5 mM, most preferably from about
10 .mu.M, about 20 .mu.M, or about 50 .mu.M to about 100 .mu.M,
about 150 .mu.M, or about 200 .mu.M.
[0379] D) Home Health Care/Hygiene Product Formulations.
[0380] In certain embodiments, one or more of the targeting
peptide(s), and/or antimicrobial peptides (AMPs) and/or chimeric
moieties, and/or STAMPS described herein are incorporated into
healthcare formulations, e.g., for home use. Such formulations
include, but are not limited to toothpaste, mouthwash, tooth
whitening strips or solutions, contact lens storage, wetting, or
cleaning solutions, dental floss, toothpicks, toothbrush bristles,
oral sprays, oral lozenges, nasal sprays, aerosolizers for oral
and/or nasal application, wound dressings (e.g., bandages), and the
like.
[0381] For example, chimeric moieties and/or STAMPs, and/or AMPs
directed against S. mutans are well suited for inhibiting frequency
or severity of dental caries formation, plaque formation,
periodontal disease, and/or halitosis.
[0382] Chimeric moieties and/or STAMPs, and/or AMPs directed
against Corynebacterium spp, when applied to a skin surface can
reduce/eliminate Corynebacterium resulting in a reduction of odors.
Such moieties are readily incorporated in soaps, antibiotics,
antiseptics, disinfectants, and the like.
[0383] The formulation of such health products is well known to
those of skill, and the antimicrobial peptides and/or chimeric
constructs are simply added to such formulations in an effective
dose (e.g., a prophylactic dose to inhibit dental carie formation,
etc.).
[0384] For example, toothpaste formulations are well known to those
of skill in the art. Typically such formulations are mixtures of
abrasives and surfactants; anticaries agents, such as fluoride;
tartar control ingredients, such as tetrasodium pyrophosphate and
methyl vinyl ether/maleic anhydride copolymer; pH buffers;
humectants, to prevent dry-out and increase the pleasant mouth
feel; and binders, to provide consistency and shape (see, e.g.,
Table 17). Binders keep the solid phase properly suspended in the
liquid phase to prevent separation of the liquid phase out of the
toothpaste. They also provide body to the dentifrice, especially
after extrusion from the tube onto the toothbrush.
TABLE-US-00017 TABLE 17 Typical components of toothpaste.
Ingredients Wt % Humectants 40-70 Water 0-50 Buffers/salts/tartar
0.5-10 control Organic thickeners 0.4-2 (gums) Inorganic thickeners
0-12 Abrasives 10-50 Actives (e.g., triclosan) 0.2-1.5 Surfactants
0.5-2 Flavor and sweetener 0.8-1.5 Fluoride sources provide
1000-15000 ppm fluorine.
[0385] Table 18 lists typical ingredients used in formulations; the
final combination will depend on factors such as ingredient
compatibility and cost, local customs, and desired benefits and
quality to be delivered in the product. It will be recognized that
one or more antimicrobial peptides and/or chimeric constructs
described herein can simply be added to such formulations or used
in place of one or more of the other ingredients.
TABLE-US-00018 TABLE 18 List of typical ingredients. Tartar
Inorganic Control Gums Thickeners Abrasives Surfactants Humectants
Ingredient Sodium Silica Hydrated Sodium Glycerine Tetrasodium
carboxymethyl thickeners silica lauryl sulfate pyrophosphate
cellulose Cellulose ethers Sodium Dicalcium Sodium N- Sorbitol
Gantrez S-70 aluminum phosphate lauryl silicates digydrate
sarcosinate Xanthan Gum Clays Calcium Pluronics Propylene Sodium
tri- carbonate glycol polyphosphate Carrageenans Sodium Xylitol
bicarbonate Sodium alginate Calcium Sodium Polyethylene
pyrophosphate lauryl glycol sulfoacetate Carbopols Alumina
[0386] One illustrative formulation described in U.S. Pat. No.
6,113,887 comprises (1) a water-soluble bactericide selected from
the group consisting of pyridinium compounds, quaternary ammonium
compounds and biguanide compounds in an amount of 0.001% to 5.0% by
weight, based on the total weight of the composition; (2) a
cationically-modified hydroxyethylcellulose having an average
molecular weight of 1,000,000 or higher in the
hydroxyethylcellulose portion thereof and having a cationization
degree of 0.05 to 0.5 mol/glucose in an amount of 0.5% to 5.0% by
weight, based on the total weight of the composition; (3) a
surfactant selected from the group consisting of polyoxyethylene
polyoxypropylene block copolymers and alkylolamide compounds in an
amount of 0.5% to 13% by weight, based on the total weight of the
composition; and (4) a polishing agent of the non-silica type in an
amount of 5% to 50% by weight, based on the total weight of the
composition. In certain embodiments, the antimicrobial peptide(s)
and/or chimeric construct(s) described herein can be used in place
of the bactericide or in combination with the bactericide.
[0387] Similarly, mouthwash formulations are also well known to
those of skill in the art. Thus, for example, mouthwashes
containing sodium fluoride are disclosed in U.S. Pat. Nos.
2,913,373, 3,975,514, and 4,548,809, and in US Patent Publications
US 2003/0124068 A1, US 2007/0154410 A1, and the like. Mouthwashes
containing various alkali metal compounds are also known: sodium
benzoate (WO 9409752); alkali metal hypohalite (US 20020114851A1);
chlorine dioxide (CN 1222345); alkali metal phosphate (US
2001/0002252 A1, US 2003/0007937 A1); hydrogen sulfate/carbonate
(JP 8113519); cetylpyridium chloride(CPC) (see, e.g., U.S. Pat. No.
6,117,417, U.S. Pat. No. 5,948,390, and JP 2004051511). Mouthwashes
containing higher alcohol (see, e.g., US 2002/0064505 A1, US
2003/0175216 A1); hydrogen peroxide (see, e.g., CN 1385145);
CO.sub.2 gas bubbles (see, e.g., JP 1275521 and JP 2157215) are
also known. In certain embodiments, these and other mouthwash
formulations can further comprise one or more of the AMPs or
compound AMPs of this invention.
[0388] Contact lens storage, wetting, or cleaning solutions, dental
floss, toothpicks, toothbrush bristles, oral sprays, oral lozenges,
nasal sprays, and aerosolizers for oral and/or nasal application,
and the like are also well known to those of skill in the art and
can readily be adapted to incorporate one or more antimicrobial
peptide(s) and/or chimeric construct(s) described herein.
[0389] The foregoing pharmaceutical and/or home healthcare
formulations and/or devices are meant to be illustrative and not
limiting. Using teaching provided herein, the antimicrobial
peptide(s) and/or chimeric construct(s) described herein can
readily be incorporated into other products.
[0390] E) Illustrative Oral Care Formulations.
[0391] The targeting peptide(s), and/or antimicrobial peptide(s),
and/or chimeric moieties, and/or STAMPs described herein can be
used for a number of applications, e.g., as described above. In
certain embodiments anti-S. mutans STAMPs, AMPs, and/or other
chimeric moieties can be used to reduce the incidence or severity
of dental caries, inhibit plaque formation, reduce halitosis, and
the like. Accordingly, in certain embodiments, such moieties are
included in devices and formulations for dental applications e.g.,
tea or other drinks, toothpick coatings, dental floss coatings,
toothpaste, gel, mouthwash, varnish, even professional dental
products.
[0392] In certain embodiments, methods of treating or reducing the
incidence, duration, or severity of periodontal disease are
provided. The methods can include applying to the gingival crevice
or periodontal pocket a composition comprising a targeting peptide,
and/or antimicrobial peptide, and/or STAMP, and/or other chimeric
moiety as described herein with a carrier/stabilizing agent. In the
composition applied, the carrier/stabilizing agent can provide
retention, tissue penetration, deposition and sustained release of
the active agent (e.g., STAMP) for reducing the population of
specific bacterial species within a periodontal biofilm and
associated tissues. In certain embodiments, the carrier agent
provides penetration and retention into the gingival crevice or
periodontal pocket and associated tissues with sustained release of
the active agent to enhance the reduction in population of select
bacteria within the gingival tissue and dentinal tubule tissue.
[0393] In various embodiments, carrier agents can include, but are
not limited to polylactide, polyglycolide,
polylactide-co-glycolide, polycaprolactone, cellulosic-based
polymers, ethylene glycol polymers and its copolymers, oxyethylene
polymers, polyvinyl alcohol, chitosan and hyaluronan and its
copolymers. In an aspect, the carrier agents include hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol,
polyethylene oxide, ethylene oxide-propylene oxide co-polymers,
chitosan, hyaluronan and its copolymers, or combinations thereof.
In another aspect, the carrier agents include hyaluronan or
hyaluronic acid and copolymers including salts of hyaluronic acid,
esters of hyaluronic acid, cross-linked gels of hyaluronic acid,
enzymatic derivatives of hyaluronic acid, chemically modified
derivatives of hyaluronic acid or combinations thereof. As used
herein, hyaluronic acid broadly refers to naturally occurring,
microbial and synthetic derivatives of acidic polysaccharides of
various molecular weights constituted by residues of D-glucuronic
acid polysaccharides and N-acetyl-D-glucosamine.
[0394] In certain embodiments, the active agent (e.g., STAMP, AMP,
etc.) and the carrier agent are in the form of an admixture, in the
form of a complex, covalently coupled, or a combination thereof. In
certain embodiments, the carrier agent comprises a bioadhesive.
Suitable bioadhesive carrier agents include, but are not limited to
a cellulose based polymer and/or a dextrin. Suitable cellulose
based polymers include, but are not limited to hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, or a
mixture thereof. In one illustrative embodiment, the bioadhesive
carrier agent includes polylactide, polyglycolide,
polylactide-co-glycolide, polyethylene glycol, hyaluronan,
hyaluronic acid, chitosan, or a mixture thereof. In certain
embodiments the bioadhesive carrier agent can include a copolymer
comprising polyethylene glycol, hyaluronan, hyaluronic acid,
chitosan, or a mixture thereof.
[0395] In certain embodiments, the carrier agent penetrates
periodontal tissues. Suitable penetrating carrier agents include,
but are not limited to hyaluronic acid, a hyaluronic acid
derivative, chitosan, a chitosan derivative, or a mixture thereof.
In an embodiment, the penetrating carrier agent includes a salt of
hyaluronic acid, an ester of hyaluronic acid, an enzymatic
derivative of hyaluronic acid, a cross-linked gel of hyaluronic
acid, a chemically modified derivative of hyaluronic acid, or a
mixture thereof.
V. Microorganism Detection.
[0396] As indicated above, the targeting moieties and/or STAMPs are
useful in diagnostic compositions and methods to determine the
presence or absence and/or to quantify the amount of one or
microorganisms present in the environment, in a food stuff, in a
biological sample, and the like.
[0397] For example, targeting peptide-antimicrobial peptide
conjugates (e.g. Specifically targeted antimicrobial peptides
(STAMPs)) can be used as diagnostic reagents. STAMPs (and other
targeted antimicrobial constructs described herein) have the
ability to specifically bind to microorganisms, for example, S.
mutans, and permeabilize or disrupt their membrane such that cell
impermeable dyes or other reagent (propidium iodide, etc.) may
enter the microorganism or intracellular molecules or contents
(ATP, DNA, Calcium, etc.) of the targeted microorganism are caused
to be released into the environment for analysis. In one method a
STAMP, for example, C16G2, can permeabilize or disrupt the membrane
of target microorganisms, for example, S. mutans, in a prepared
culture or clinical sample by itself, in a biofilm in vitro or in
vivo. To the sample a cell impermeable dye (e.g. propidium iodide,
etc.) is added to label and allow for detection of those
microorganisms targeted by the STAMP. Cell permeable dyes (e.g.
SYTO9) can also be added to label and detect the entire population
of microorganisms in the sample. Labeled cells can then be
quantified by fluorescence microscopy, fluorometry, flow cytometry
or other method.
[0398] In another example, a STAMP treated sample is mixed with
luciferase and luciferin which reacts with the ATP released from
the STAMP treated cells and the resulting luminescence is used to
detected and quantify targeted cells.
VI. Kits.
[0399] In another embodiment this invention provides kits for the
inhibition of an infection and/or for the treatment and/or
prevention of dental caries in a mammal. The kits typically
comprise a container containing one or more of the active agents
(i.e., the antimicrobial peptide(s) and/or chimeric construct(s))
described herein. In certain embodiments the active agent(s) can be
provided in a unit dosage formulation (e.g., suppository, tablet,
caplet, patch, etc.) and/or may be optionally combined with one or
more pharmaceutically acceptable excipients.
[0400] In certain embodiments the kits comprise one or more of the
home healthcare product formulations described herein (e.g.,
toothpaste, mouthwash, tooth whitening strips or solutions, contact
lens storage, wetting, or cleaning solutions, dental floss,
toothpicks, toothbrush bristles, oral sprays, oral lozenges, nasal
sprays, aerosolizers for oral and/or nasal application, and the
like).
[0401] In certain embodiments kits are provided for detecting
and/or locating and/or quantifying certain target microorganisms
and/or cells or tissues comprising certain target microorganisms,
and/or prosthesis bearing certain target microorganisms, and/or
biofilms comprising certain target microorganisms. In various
embodiments these kits typically comprise a chimeric moiety
comprising a targeting moiety and a detectable label as described
herein and/or a targeting moiety attached to an affinity tag for
use in a pretargeting strategy as described herein.
[0402] In addition, the kits optionally include labeling and/or
instructional materials providing directions (i.e., protocols) for
the practice of the methods or use of the "therapeutics" or
"prophylactics" or detection reagents of this invention. Certain
instructional materials describe the use of one or more active
agent(s) of this invention to therapeutically or prophylactically
to inhibit or prevent infection and/or to inhibit the formation of
dental caries. The instructional materials may also, optionally,
teach preferred dosages/therapeutic regiment, counter indications
and the like.
[0403] While the instructional materials typically comprise written
or printed materials they are not limited to such. Any medium
capable of storing such instructions and communicating them to an
end user is contemplated by this invention. Such media include, but
are not limited to electronic storage media (e.g., magnetic discs,
tapes, cartridges, chips), optical media (e.g., CD ROM), and the
like. Such media may include addresses to internet sites that
provide such instructional materials.
EXAMPLES
[0404] The following examples are offered to illustrate, but not to
limit the claimed invention.
Example 1
Design and Activity of a "Dual-Targeted" Antimicrobial Peptide
[0405] Numerous reports have indicated the important role of human
normal flora in the prevention of microbial pathogenesis and
disease. Evidence suggests that infections at mucosal surfaces
result from the outgrowth of subpopulations or clusters within a
microbial community, and are not linked to one pathogenic organism
alone. In order to preserve the protective normal flora while
treating the majority of infective bacteria in the community, a
tunable therapeutic is necessary that can discriminate between
benign bystanders and multiple pathogenic organisms. Here we
describe the proof-of-principle for such a multi-targeted
antimicrobial: a multiple-headed specifically-targeted
antimicrobial peptide (MH-STAMP). The completed MH-STAMP,
M8(KH)-20, displays specific activity against targeted organisms in
vitro (Pseudomonas aeruginosa and Streptococcus mutans) and can
remove both species from a mixed planktonic culture with little
impact against untargeted bacteria. These results demonstrate that
a functional, dual-targeted molecule can be constructed from
wide-spectrum antimicrobial peptide precursor.
Introduction
[0406] For nearly 30 years antimicrobial peptides (AMPs) have been
rigorously investigated as alternatives to small molecule
antibiotics and potential solutions to the growing crisis of
antibiotic resistant bacterial infections (Ganz (2003) Nat Rev
Immunol., 3: 710-720; Hancock and Lehrer (1998)., 16: 82-88).
Numerous reports have characterized potential AMPs from natural
sources, and a great body of work has been carried out designing
"tailor-made" AMPs due to the approachable nature of solid-phase
peptide synthesis (SPPS) (Genco et al. (2003) Int J Antimicrob
Agents, 21: 75-78; He and Eckert (2007) Antimicrob Agents
Chemother., 51: 1351-1358). Several examples of the latter have
shown remarkable activities in vitro against fungi, Gram-positive
and Gram-negative bacteria, as well as some enveloped viruses
(Brogden (2005) Nat Rev Microbiol. 3: 238-250).
[0407] Unlike small molecule antibiotics that may lose activity
when their basic structures are modified even incrementally,
peptides are a convenient canvas for molecular alteration. AMPs can
be optimized through the incorporation of more or less hydrophobic
or charged amino acids, which has been shown to affect selectivity
for Gram-positive, Gram-negative or fungal membranes (Muhle and Tam
JP (2001) Biochemistry, 40: 5777-5785; Tossi et al. (2000)
Biopolymers 55: 4-30). Additionally, lysine residues can be
utilized to improve AMP activity per .mu.M. In this approach,
multiple AMP chains can be attached to a single peptide scaffold
through branching from lysine epsilon-amines (Tam et al. (2992)
Eur. J. Biochem., 269: 923-932; Pini et al. (2005) Antimicrob
Agents Chemother., 2005; 49: 2665-2672). AMP activity can be
specifically tuned through the attachment of a targeting peptide
region, as described for a novel class of molecules, the
specifically-targeted antimicrobial peptides, or STAMPs (Eckert et
al. (2006) Antimicrob Agents Chemother., 50: 3651-3657; Eckert et
al. (2006) Antimicrob Agents Chemother., 50: 1480-1488). These
chimeric molecules can consist of functionally independent
targeting and killing moieties within a linear peptide sequence. A
pathogenic bacterium recognized (i.e. bound) by the targeting
peptide can be eliminated from a multi-species community with
little impact to bystander normal flora. As an extension of this
concept, we hypothesized that a STAMP could be constructed with
multiple targeting peptide "heads" attached to a single AMP by
utilizing a central lysine residue branch point. Potentially,
targeting "heads" could be specific for the same pathogen, or have
different binding profiles. Utilizing the former approach,
microbial resistance evolution linked to a targeting peptide could
be inhibited or reduced, as no single microbial population would
have the genetic diversity necessary to mutate multiple discrete
targeting peptide receptors in one cell (Drake et al. (1998)
Genetics 148: 1667-1686).
[0408] Multi-headed STAMP (MH-STAMP) molecules with differing
bacterial targets may have appeal in treating poly-microbial
infections, or where it may be advantageous to remove a cluster of
biofilm constituents without utilizing several distinct molecules;
for example in the simultaneously treatment of dental caries and
periodontitis, or in the eradication of the Propionibacteria spp.
and Staphylococcus spp. involved in acne and skin infections,
respectively.
[0409] In this example, we present the proof-of-principle design,
synthesis and in vitro activity of such a MH-STAMP, M8(KH)-20.
Previously, we identified two functional STAMP targeting domains,
one with specific recognition of the cariogenic pathogen S. mutans
(Eckert et al. (2006) Antimicrob Agents Chemother., 50: 3651-3657),
and the other with Pseudomonas spp.-level selectivity (Eckert et
al. (2006) Antimicrob Agents Chemother., 50: 3833-3838). Conjoined
to a normally wide-spectrum linear AMP, we observed antimicrobial
effects directed specifically to P. aeruginosa and S. mutans in
vitro. Additionally, treatment of mixed bacterial communities with
the multi-headed MH-STAMP resulted in the specific eradication of
the target organisms with little impact on bystander population
levels.
Materials and Methods
[0410] Bacterial Strains and Growth Conditions
[0411] P. aeruginosa ATCC 15692, Klebsiella pneumoniae KAY 2026
(Sprenger and Lengeler (1984) J Bacteriol., 157: 39-45),
Escherichia coli DH5a (pFW5, spectinomycin resistance) (Podbielski
et al. (1996) Gene, 177: 137-147), Staphylococcus aureus Newmann
(Duthie and Lorenz (1952) J Gen Microbiol., 6: 95-107), and
Staphylococcus epidermidis ATCC 35984 were cultivated under aerobic
conditions at 37.degree. C. with vigorous shaking Aerobic
Gram-negative organisms were grown in Lauri-Bertaini (LB) broth and
Gram-positive bacteria in Brain-heart infusion (BHI) broth.
Streptococcus mutans JM11 (spectinomycin resistant, UA140
background) was grown in Todd-Hewitt (TH) broth under anaerobic
conditions (80% N2, 15% CO.sub.2, 5% H2) at 37.degree. C. Merritt
et al. (2005) J Microbiol Meth., 61: 161-170. All bacteria were
grown overnight to an OD600 of 0.8-1.0 prior to appropriate
dilution and antimicrobial testing.
[0412] Synthesis of Multi-Head STAMP Peptides
[0413] Conventional solid-phase peptide synthesis (SPPS)
methodologies were utilized for the construction of all peptides
shown in FIG. 15 (Symphony Synthesizer, PTI, Tucson, Ariz.).
Chemicals, amino acids, and synthesis resins were purchased from
Anaspec (San Jose, Calif.). BD2.20 (FIRKFLKKWLL (SEQ ID NO:3226),
amidated c-terminus, mw 1491.92), an antimicrobial peptide
developed in our laboratory with robust antimicrobial activity
against a number of bacterial species (Table 19), served as the
root sequence to which differing targeting peptides were attached:
Firstly, BD2.20 was synthesized by SPPS (Rink-Amide-MBHA resin,
0.015 mmol), followed by the stepwise coupling of a functionalized
alkane (NH.sub.2(CH.sub.2).sub.7COOH), and an Fmoc-protected Lys
(side-chain protected with 4-methyltrityl (Mtt)) to the N-terminus.
Standard SPPS methods were then employed for the step-wise addition
of the S. mutans targeting peptide M8 plus a tri-Gly linker region
(TFFRFLNR-GGG (SEQ ID NO:3227)) to the N-terminal of the central
Lys. After assembly of Fmoc-M8-GGG-K(Mtt)-(CH.sub.2).sub.7CO-BD2.20
(SEQ ID NO:3228), the Fmoc group was removed with 25% piperidine in
DMF and the N-terminal was re-protected with an acetyl group with
Ac.sub.2O/DIEA (1:1, 20 molar excess) for 2 hours. The
Mtt-protected amino group of the central Lys was then selectively
exposed with 2% TFA in DCM (1.5 mL) for 15 minutes (three cycles of
5 min). The resulting product was reloaded into the synthesizer and
the peptide sequence built from the Lys side-chain was completed
with standard Fmoc SPPS methods. As shown in FIG. 15, the completed
MH-STAMP M8(KH)-20 contained the side-chain peptide KH (Pseudomonas
spp.-targeting, KKHRKHRKHRKH-GGG (SEQ ID NO:3229)), while in
MH-STAMP M8(BL)-20a peptide with no bacterial binding (data not
shown), BL-1 (DAANEA-GGG), was utilized. BL(KH)-20 was constructed
identically to M8(KH)-20, utilizing BL-1 in place of M8 (FIG.
15).
TABLE-US-00019 TABLE 19 MICs of MH-STAMPs and component peptides.
MIC (.mu.M) P. aeruginosa E. coli K. pneumoniae S. mutans S.
epidermidis S. aureus BD2.20 14.4 .+-. 4.40 5.47 .+-. 1.41 2.98
.+-. 0.47 2.86 .+-. 0.60 5.11 .+-. 1.58 5.625 .+-. 1.29 M8(KH)-
11.95 .+-. 3.32 2.72 .+-. 0.59 3.13 6.25 3.13 5.64 .+-. 1.07 20
M8(BL)- 50 5.97 .+-. 0.94 6.88 .+-. 1.98 6.25 6.25 18.05 .+-. 6.58
20 BL(KH)- 27.5 .+-. 7.90 6.25 6.25 6.25 6.25 6.25 20 Average MIC
with standard deviation, n = 10 assays.
[0414] Synthesis progression was monitored by the ninhydrin test,
and completed peptides cleaved from the resin with 95% TFA
utilizing appropriate scavengers, and precipitated in methyl
tert-butyl ether. Purification and MH-STAMP quality was confirmed
by HPLC (Waters, Milford, Mass.) using a linear gradient of
increasing mobile phase (acetonitrile 10 to 90% in water with 0.1%
TFA) and a Waters XBridge BEH 130 C18 column (4.6.times.100 mm,
particle size 5 .mu.m). Absorbance at 215 nm was utilized as the
monitoring wavelength, though 260 and 280 nm were also collected.
LC spectra were analyzed with MassLynx Software v.4.1 (Waters).
Matrix-assisted laser desorption ionization (MALDI) mass
spectroscopy was utilized to confirm correct peptide mass (Voyager
System 4291, Applied Biosystems) (Anderson et al. (2008) Biotechnol
Lett., 30: 813-818).
[0415] MIC Assay
[0416] Peptides were evaluated for basic antimicrobial activity by
broth microdilution, as described previously (Eckert et al. (2006)
Antimicrob Agents Chemother., 50: 3651-3657; Eckert et al. (2006)
Antimicrob Agents Chemother., 50: 1480-1488). Briefly,
.about.1.times.105 cfu/mL bacteria were diluted in TH (S. mutans),
or Mueller-Hinton (MH) broth (all other organisms) and distributed
to 96-well plates. Serially-diluted (2-fold) peptides were then
added and the plates incubated at 37.degree. C. for 18-24 h.
Peptide MIC was determined as the concentration of peptide that
completely inhibited organism growth when examined by eye (clear
well). All experiments were conducted 10 times.
[0417] Post-Antibiotic Effect Assay
[0418] The activity and selectivity of MH-STAMPs after a 10 min
incubation was determined by growth retardation experiments against
targeted and untargeted bacteria in monocultures, as described
previously (Id.). Cells from overnight cultures were diluted to
.about.5.times.106 cfu/mL in MH (or TH with 1% sucrose for S.
mutans), normalized by OD600 0.05-0.1 and seeded to 96-well plates.
Cultures were then grown under the appropriate conditions for 2 h
(3 h for S. mutans) prior to the addition of peptides for 10 min.
Plates were then centrifuged at 3000.times.g for 5 min, the
supernatants discarded, fresh medium returned (MH or TH without
sucrose for S. mutans), and incubation resumed. Bacterial growth
after treatment was then monitored over time by OD600.
[0419] Microbial Population Shift Assay
[0420] Mixed planktonic populations of P. aeruginosa, E. coli, S.
epidermidis, and S. mutans were utilized to examine the potential
of MH-STAMPs to direct species composition within a culture after
treatment. Samples were prepared containing:
.about.6.times.10.sup.4 cfu/mL S. mutans, .about.2.times.10.sup.4
cfu/mL E. coli, .about.2.times.10.sup.4 cfu/mL S. epidermidis, and
.about.0.5.times.10.sup.4 cfu/mL P. aeruginosa in BHI (mixed
immediately before peptide addition). Peptide (10 .mu.M) or
mock-treatment (1.times.PBS) was then added and samples were
incubated at 37.degree. C. for 24 h under anaerobic conditions (80%
N.sub.2, 15% CO.sub.2, 5% H.sub.2). After incubation, samples were
serially diluted (1:10) in 1.times.PBS and aliquots from each
dilution were then spotted to agar plates selective for each
species in the mixture: TH plus 800 .mu.g/mL spectinomycin (S.
mutans), LB plus 25 .mu.g/mL ampicillin (P. aeruginosa), LB plus
200 .mu.g/mL spectinomycin (E. coli), and mannitol salt agar (MSA,
S. epidermidis) in order to quantitate survivors from each species.
Plates were then incubated 37.degree. C. under aerobic conditions
(TH plates were incubated anaerobically) and colonies counted after
24 h to determine survivors. Expected colony morphologies were
observed for each species when plated on selective media. Gram
stains and direct microscopic observation (from select isolated
colonies) were undertaken to confirm species identity (data not
shown). The detection limit of the assay was 200 cfu/mL.
Results
[0421] Design and Synthesis of Multi-Headed STAMPs
[0422] We constructed a prototype MH-STAMP from the
well-established targeting peptides KH (specific to Pseudomonas
spp) and M8 (specific for Streptococcus mutans). The wide-spectrum
antimicrobial peptide BD2.20 was utilized as the base AMP for all
MH171 STAMP construction. BD2.20 is a novel synthetic AMP with a
cationic and amphipathic residue arrangement, which has robust MICs
against a variety of Gram-negative and Gram-positive organisms
(Table 19). For the synthesis of MH-STMAP M8(KH)-20 (construct
presented in FIG. 15), BD2.20 and a Lys (Mtt-protected side-chain)
residue were joined via an activated alkane spacer, followed by
addition of the M8 targeting peptide to the N-terminus of the
product. Selective deprotection of the central Lys(Mtt) side chain
was then undertaken and the KH targeting peptide attached. The
correct molecular mass (4888.79) and .about.90% purity was
confirmed by HPLC and MALDI mass spectrometry (FIG. 16).
[0423] The non-binding "blank" targeting peptide BL-1 was
incorporated into the synthesis scheme in place of KH or M8 to
construct variant MH-STAMPs possessing a single functional
targeting head: M8(BL)-20 and BL(KH)-20. The correct MW and
acceptable purity were observed for these MH-STAMPs (FIG. 15, data
not shown).
[0424] General Antimicrobial Activity of Multi-Head Constructs
[0425] After synthesis, the completed MH-STAMPs were evaluated for
general antimicrobial activity by MIC against a panel of bacteria.
As shown in Table 19, the MH-STAMP constructs M8(KH)-20, BL(KH)-20,
and M8(BL)-20 were found to have similar activity profiles to that
of BD2.20 for the organisms examined (less than two titration steps
in 10-fold difference). Additionally, we observed a difference in
general susceptibility between P. aeruginosa and the other
organisms tested, suggesting this bacterium is more resistant to
BD2.20. Overall, these data indicate that the addition of the
targeting domains to the base sequence was tolerated and did not
completely inhibit the activity of the antimicrobial peptide.
[0426] Peptide selectivity could not be determined utilizing these
methods, as STAMPs and their parent AMP molecules often display
similar MICs, but have radically different antimicrobial kinetics
and selectivity due to increased specific-killing mediated by the
targeting regions (Id.). Therefore, we performed different
experiments to test for antimicrobial selectivity and functional
MH-STAMP construction.
[0427] Selectivity and Post-Antibiotic Effect of MH-STAMP
Constructs
[0428] MH-STAMP antimicrobial kinetics was ascertained utilizing a
variation of the classical post-antibiotic effect assay, which
measures the ability of an agent to affect an organism's growth
after a short exposure period. Monocultures of MH-STAMP-targeted
and untargeted organisms were exposed to M8(KH)-20, M8(BL)-20,
BL(KH)-20, or unmodified BD2.20, then allowed to recover. As shown
in FIG. 17A, S. mutans growth was effectively retarded by
M8-containing constructs (M8(KH)-20, M8(BL)-20), but was not
altered by a MH-STAMP construct lacking this region (BL(KH)-20).
Similarly, the growth of the other targeted bacterium, P.
aeruginosa, was inhibited in a KH-dependant manner (FIG. 17B). In
comparison, the non-targeted bacteria E. coli, S. aureus, and S.
epidermidis were not inhibited by treatment with any MH-STAMP and
were only inhibited by the base antimicrobial peptide BD2.20, which
displayed robust antimicrobial activity against all examined
strains. These results indicate that MH-STAMPs containing KH or M8
targeting domains have activity against P. aeruginosa or S. mutans,
respectively, and not other bacteria. Furthermore, replacement of
the targeting region with a non-binding peptide abolishes specific
activity.
[0429] Ability of MH-STAMPs to Direct a "Population Shift" within a
Mixed Species Population
[0430] We hypothesized that potential MH-STAMP dual-functionality
could affect a particular set of bacteria within a mixed
population, thereby promoting the outgrowth of non-targeted
organisms and "shifting" the constituent makeup. To examine this
possibility, defined mixed populations of planktonic cells were
treated continuously and the make-up of the community examined
after 24 h. As shown in FIG. 18, treatment with the wide spectrum
AMP BD2.20 resulted in a significant loss of recoverable cfu/mL
after 24 h from all species in the mixture. Treatment with
M8(KH)-20 was found to alter this pattern; we observed
.about.1.times.10.sup.5 cfu/mL surviving E. coli and S.
epidermidis, but did not recover S. mutans or P. aeruginosa cfu/mL.
In BL(KH)-20 treated samples, P. aeruginosa cfu/mL were not
observed, though we recovered higher than input cfu/mL from S.
mutans and unchanged numbers of S. epidermidis and E. coli. In
samples exposed to M8(BL)-20, S. mutans recoverable cfu/mL were
greatly reduced compared to input cfu/mL, while other species were
not affected or affected to a lesser extent. Interestingly, these
results suggest that M8(KH)-20, M8(BL)-20, and BL(KH)-20 retain
their ability to affect organisms recognized by the targeting
regions present, even within a mixed population of bacteria.
Discussion
[0431] Our results indicate that we have successfully constructed a
STAMP with dual antimicrobial specificities controlled by the
targeting peptides present in the molecule; KH for Pseudomonas spp,
M8 for S. mutans. In a closed multi-species system (FIG. 18), the
dual specificity of M8(KH)-20 was readily discernable: the
population of the culture "shifted" away from targeted organisms
after MH-STAMP treatment. The targeted bacteria were eliminated and
the population of untargeted organisms increased, to varying
degrees, above-input cfu/mL. Additionally, interruption of KH or M8
in the MH-STAMP construct with the non-binding peptide BL-1
resulted in the expected elimination of only one targeted species.
These results support the hypothesis that functional MH-STAMPs
could be constructed from a wide-spectrum AMP base.
[0432] The emergence of metagenomics and the development of more
sensitive molecular diagnostics has driven an increase in the
understanding of human-associated microbial ecologies and
host-microbe interactions (Aas et al. (2005) J Clin Microbiol., 43:
5721-5732; Boman (2000) Immunol Rev., 173: 5-16; Kreth et al.
(2005) J Bacteriol., 187: 7193-7203). At mucosal surfaces, it has
become clear that our bodies harbor an abundance of residential
flora which may impact innate and humoral immunity, nutrient
availability, protection against pathogens, and even host
physiology (Metges (2000) J Nutr., 130: 1857S-64; Sears (2005)
Anaerobe, 11: 247-251; Lievin-Le et al. (2006) Clin Microbiol Rev.,
19: 315-337; DiBaise et al. (2008) Mayo Clinic Proceedings 83:
460-469). Furthermore, findings have indicated that shifts in the
diversity of normal flora are associated with negative clinical
consequences; for example the overgrowth of S. mutans in the oral
cavity during cariogenesis (linked to the uptake of sucrose) or the
antibiotic-assisted colonization of the intestine by Clostridium
difficle (Loesche (1986) Microbiol Rev., 50: 353-380; Gould and
McDonald (2998) Crit Care 12: 203). Other population shifts may be
linked to axilla odor (Corynebacteria spp) (Leyden et al. (1981) J
Invest Dermatol., 77: 413-416; Elsner (2006) Curr Probl Dermatol.,
33: 35-41), or even host obesity. Given the quantity and diversity
of microbes present, pathogenesis at mucosal surfaces is not likely
to be associated with the overgrowth of a single strain or species.
More often, it is a population shift resulting in the predominance
of two or more species; for example the persistence of Burkholderia
cepacia and P. aeruginosa in cystic fibrosis airway or Treponema
denticola and Porphymonas gingivalis and other "red cluster"
organisms in gingivitis (Govan and Deretic (1996) Microbiol Rev.,
60: 539-574; Paster et al. (2001) J Bacteriol., 183: 3770-3783). In
many cases (such as the latter) these species may have only distant
phylogenetic relationships and display differential
susceptibilities to antibiotic therapies resulting in persistent
disease progression despite treatment (Schlessinger (1988) Clin
Microbiol Rev., 1: 54-59; Tresse et al. (1997) J Antimicrob
Chemother., 40: 419-421). Currently, available treatments for
infections of mucosal surfaces are largely non-specific
(traditional small-molecule antibiotics, mechanical removal), and
thus are not effective in retaining flora or shifting the
constituent balance back to a health-associated composition (Keene
and Shklair (1974) J Dent Res., 53: 1295). There is a need for a
therapeutic treatment that can selectively target multiple
pathogens, regardless of their phylogenetic relationship, and
MH-STAMPs can help achieve this goal.
[0433] In monoculture experiments (FIG. 17), our results suggest
that M8 or KH inclusion in the MH-STAMP drove activity towards S.
mutans or P. aeruginosa, but also that the presence of a targeting
domain reduced the activity of the parent AMP BD2.20 against
untargeted organisms. In contrast, the results of our MIC assays
(Table 19) indicate little difference in activity between BD2.20
and any MH-STAMP. Against untargeted organisms, the M8 and KH
regions are likely to have a negative, but not completely
inhibitory, impact on BD2.20 activity. Given the long duration of
activity and the lower inoculum size in the MIC assay (compared
with experiments in FIG. 17), it is likely that all
BD2.20-containing peptides could reach equal levels of growth
inhibition, despite large and target-specific differences in
antimicrobial speed. This pattern of results was also observed when
comparing MICs of targeted and untargeted organisms utilizing
STAMPs against S. mutans and Pseudomonas mendocina (Eckert et al.
(2006) Antimicrob Agents Chemother., 50: 3651-3657; Eckert et al.
(2006) Antimicrob Agents Chemother., 50: 1480-1488).
[0434] Although more rigorous studies and a more medically relevant
combination of pathogen targets is desirable, these findings
indicate that it is possible to design an antimicrobial
peptide-based therapeutic with multiple and defined fidelities in
vitro. MH-STAMPs may help improve human health through the
promotion of healthy microbial constituencies.
Example 2
Synthesis of Peptide-Porphyrin Conjugate
[0435] The mixture of coupling reagent HATU (5 eq. excess, 10 mg)
and purpurin-18 (MW 564, 5 eq excess, 15 mg) in 600 mL dry
dichloromethane (DCM):DMF:dimethylsulphoxide (DMSO) (1:1:1 (v/v))
was added to the peptide resin (1 molar equivalent, 15 mg) which
was swelled by placing in minimal DMF for 30 min prior to reaction.
26 .mu.L (10 molar equivalents) DIPEA was then added to the
reaction flask to initiate the reaction. The reaction mixture was
protected with argon and stirred at room temperature for 3 h.
[0436] After finishing, the reaction mixture was then passed down a
sintered glass filtered vial and extensively washed with DMF and
DCM to remove all waste reagents. The resin was then dried
overnight in vacuum, and cleaved with 1 ml of trifluoroacetic acid
(TFA)/thioanisole/water/EDT (10/0.5/0.5/025) for 2 hr at room
temperature, and the cleavage solution was precipitated with 10 mL
methyl-tert butyl ether. The precipitate was washed twice with the
same amount of ether.
Example 3
Synthesis of Peptide-CSA Conjugate
[0437] To the fully protected peptide (solution of B43-GGG
(FIDSFIRSF-GGG, 0.025 mmol) and tri-Boc-CSA-15 (0.0125 mol) in 300
.mu.L DMF, DCC (7.7 mg), HOBt (5.1 mg) and 13 .mu.L DIEA were added
in iced-bath. After stirred at room temperature for four days, the
reaction mixture was poured into 5 ml water and extracted with
chloroform (5.times.3 mL). The CHCl.sub.3 extract was evaporated
under vacuum and dried in a lyophilizer overnight. The dried
CHCl.sub.3 extracts was then dissolved in 1 mL DCM followed by
added 1 mL of TFA in iced-bath. The reaction mixture was further
stirred at room temperature for 2 hours and precipitated with
methyl tert-butyl ether (10 mL). The precipitate was further washed
once with the same amount ether and dried in vacuum.
Example 4
STAMPs Against Corynebacterium jeikeium and Streptococcus
mutans
[0438] This example illustrates the development of STAMPs to
selectively target and reduce or eliminate Streptococcus mutans
(dental caries) or Corynebacterium jeikeium (body odor,
opportunistic infections) from mixed microbial populations.
[0439] Axilla odor is caused by overgrowth of, and metabolite
production from, Corynebacterium spp, which replaces Staphylococcus
and Micrococcus spp associated with less odor. Current hygiene
(soaps, antibiotics, antiseptics, disinfectants) practices remove
all bacteria, allowing the ratio of Corynebacteria to normal flora
to remain high during regrowth. Deodorants and anti-perspirants are
temporary solutions that hide or even exacerbate the problem.
[0440] S. mutans is the major etiological agent of dental caries.
Current methods (tooth brushing, antiseptic mouthrinses) to treat
cariogenesis have focused on complete bacterial removal, i.e.,
elimination of S. mutans and other harmless oral bacteria. Caries
have persisted despite these methods, and in many cases, S. mutans
can become the dominant organism in the mouth. Several S. mutans
and acid-targeted approaches (probiotic replacement, saliva pH
adjustment) are under development, but none have shown clinical
efficacy.
[0441] This example describes a number of STAMPs that
preferentially or selectively reduce or eliminate S. mutans and/or
Corynebacterium spp from mixed populations.
[0442] Several lead STAMPs with specific activity against
Corynebacterium jeikeium are also disclosed herein.
[0443] The STAMPs described herein comprise functional regions
within a peptide molecule or a chemical conjugate. These regions
include a targeting region comprising one or more targeting
moieties (e.g., targeting peptides), a linker, and one or more
killing moieties (e.g., antimicrobial peptides (AMPs), porphyrins,
etc.).
[0444] The STAMPs function through the targeting region, which
selectively accumulates STAMPs, and therefore killing regions, on
or in proximity to the microorganism of interest. Other flora are
not recognized by the targeting region, and therefore avoid or have
reduced STAMP accumulation and cellular damage.
[0445] In certain embodiments, STAMPs against oral S. mutans are
best applied formulated in a mouthrinse, toothpaste, cream, gel, or
adhesive strip, and in certain preferably embodiments, are provided
in a formulation that comprises 0.5 to 2.5.times.PBS (or other
salt) and other ingredients commonly found in oral healthcare
formulations (e.g., mouthrinse formulations). Certain illustrative
formulations are shown in Table 20.
[0446] During the course of evaluating STAMPs, antimicrobial
peptides (AMPs), and binding peptides for desired activity, it was
discovered that certain formulations can attenuate or promote
peptide activity, as compared to activity levels in a default
buffer system (1.times.PBS). In some cases, 1.times.PBS may provide
the best level of activity. Below are a number of formulations that
alter, or may alter, peptide or STAMP activity. For complex buffer
systems, assume the base solvent is water unless otherwise
stated.
[0447] Formulation 1 (1.times.PBS, pH 7.4): 136.8 mM NaCl, 2.68 mM
KCl, 1.01 mM Na.sub.2HPO.sub.4, and 1.37 mM KH.sub.2PO.sub.4.
[0448] Formulation 2 (HEPES/CTAB): 20 mM HEPES
(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), 150 mM NaCl,
1 mM MgCl.sub.2, and 0.1% CTAB (Cetyl trimethylammonium
bromide).
[0449] Formulation 3 (TRIS/CTAB): 20 mM Tris
(tris(hydroxymethyl)aminomethane), pH 7.5, 150 mM NaCl, 1 mM
MgCl.sub.2, and 0.1% CTAB.
[0450] Formulation 4: 20 mM HEPES.
[0451] Formulation 5: 20 mM Tris, pH 7.5.
[0452] Formulation 6: 0.2% CTAB.
[0453] Formulation 7: 1% Glycerol.
[0454] Formulation 8: 1% Pluronic F108 (nonionic surfactant:
.alpha.-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxye-
thylene) block copolymer).
[0455] Formulation 9: 1% Pluronic F123 (Poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol),
average M.sub.n.about.5,800).
[0456] Formulation 10:1% Pluronic F17R4 (Poly(propylene
glycol)-block-poly(ethylene glycol)-block-polypropylene glycol),
average M.sub.n.about.2,700).
[0457] Formulation 11: 1% to 7% PEG400.
[0458] Formulation 12: 50 mM Urea.
[0459] Formulation 13: 10 mM AOT (Sodium
bis(2-ethylhexyl)sulfosuccinate).
[0460] Formulation 14: 0.5-0.1% Tween 20 (nonionic detergent, also
known as polysorbate 20 or PEG(20)sorbitan monolauratesorbitan
monolaurate).
[0461] Formulation 15: 0.5-0.1% Tween 80 (nonionic surfactant,
C.sub.64H.sub.124O.sub.26, also known as polyoxyethylene (20)
sorbitan monooleate, (x)-sorbitan mono-9-octadecenoate
poly(oxy-1,2-ethanediyl), or POE (20) sorbitan monooleate).
[0462] Formulation 16: 5-10% Ethanol.
[0463] Formulation 17: 20% Glycerin.
[0464] Formulation 18: 20% Sorbitol.
[0465] Formulation 19: 10% Glycerin/10% Sorbitol.
[0466] Formulation 20: 0.1% SLS (Sodium lauryl sulfate).
[0467] Formulation 21: 1% Pluronic F127 (nonionic suffactant:
.alpha.-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxye-
thylene) block copolymer).
[0468] Formulation 21: 0.1% Tween 20 (nonionic detergent, also
known as Polysorbate 20, or PEG(20)sorbitan monolaurate).
[0469] Formulation 21: 10% PG (phospholipid gel).
[0470] Mouthrinse neat solution #1 (made in 1.times.PBS): 7% ETOH,
20% Glycerin, 7% PEG 400, and 1% PLURONIC.RTM. F127.
[0471] Mouthrinse neat solution #2 (made in 1.times.PBS): 7% ETOH,
20% Sorbitol, 7% PEG 400, and 1% PLURONIC.RTM. F127.
[0472] Mouthrinse neat solution #3 (made in 1.times.PBS): 7% ETOH,
20% Glycerin and 7% PEG 400.
[0473] Mouthrinse neat solution #4 (made in 1.times.PBS): 7% ETOH,
20% Sorbitol and 7% PEG 400.
[0474] Other illustrative, but not limiting, mouthrinse
formulations are shown in Table 20.
TABLE-US-00020 TABLE 20 Illustrative mouthrinse formulations.
Rinse# ETOH Glycerin PEG400 F127 Water.sup.1 Fluoride 1 5 22.5 7 1
64.5 187.5 2 6 25 1 0 68 0 3 6 20 7 0 67 0 4 6 20 1 1 72 0 5 7 25 7
0 61 0 6 7 20 1 0 72 0 7 7 20 7 0 66 250 8 5 20 7 1 67 0 9 6.472
21.139 5.361 0.722 66.306 250 10 7 22.5 1 0 69.5 250 11 5 25 1 0 69
250 12 7 20 7 0 66 250 13 5 20 1 1 73 250 14 5 25 7 0.5 62.5 250 15
7 25 1 0.5 66.5 250 16 7 25 7 1 60 250 17 5 25 7 0.5 62.5 0 18 7 20
1 1 71 250 19 6 25 1 1 67 250 20 7 25 7 1 60 125 21 5 25 1 0 69 250
22 5 20 1.5 0.5 73 0 23 7 20 1 1 71 250 24 6 20 1 0 73 250 25 5
22.333 3.778 0.444 68.444 125 26 7 25 1 1 66 0 27 6 25 7 0 62 250
28 7 20 7 1 65 0 29 7 25 4 1 63 62.5 30 5 25 4 0 66 0 31 5 25 1 1
68 0 32 7 25 7 1 60 0 33 7 22.5 4 0.5 66 0 34 5 20 4.5 0 70.5 250
35 5 23 1 0 71 62.5 36 6 20 1 1 72 0 37 5 20 7 1 67 250 38 7 20 1 0
72 0 39 5 25 4 1 65 250 40 5 22.5 7 0 65.5 0 n1 7 20 7 1 65 0 n2 7
20% 7 1 65 0 Sorbitol n3 7 20 7 0 66 0 n4 7 20% 7 0 66 0 Sorbitol
.sup.11xPBS can be substituted for water
[0475] In certain embodiments, Corynebacterium-specific STAMPs are
formulated in any number of creams, nanoemulsions, lipid micelles,
aqueous or no-aqueous gels, sprays, soaps or roll-on bars, or other
products used for axilla or other hygiene.
[0476] STAMP-mediated selective antimicrobial activity can result
in preservation of the normal flora at the oral or axilla mucosal
surface, resulting in protective colonization and the conversion of
a harmful flora to a beneficial one. Recurrence of pathogen
overgrowth would be reduced, which also limits the amount and
frequency (and therefore cost) of STAMP delivery. STAMPs allow for
"surgical" antimicrobial precision, which limits antimicrobial
resistance evolution as well due to the general mechanism of cell
membrane damage mediated by the killing region.
[0477] A number of anti-S. mutans STAMPs (see Table 21) and anti-C.
jeikeium STAMPs have been designed and tested, some in
formulations. All show potent selective activity against their
bacterial targets in vitro, including against biofilm forms. When
tested, STAMPs have little cytotoxicity against cell lines in
vitro.
TABLE-US-00021 TABLE 21 Illustrative anti-S. mutans STAMPs. SEQ ID
STAMP Amino Acid Sequence NO 2_1G2 FIKHFIHRFGGGKNLRIIRKGIHIIKKY*
3230 C16AF5 TFFRLFNRSFTQALGKGGGFLKFLKKFFKKLKY* 3231 1845L621
KFINGVLSQFVLERKPYPKLFKFLRKHLL* 3232 1903-21 NIFEYFLEGGGKLFKFLRKHLL*
3233 Single underline is binding peptide. Double underline is
antimicrobial peptide (AMP). No underline is linker. *indicates
optionally protected (e.g., amidated) C terminal.
TABLE-US-00022 TABLE 22 Illustrative anti-C. jeikeium STAMPs.
Single underline is binding peptide. Double underline is
antimicrobial peptide (AMP). No underline is linker. *indicates
optionally protected (e.g., amidated) C terminal. STAMP Amino Acid
Sequence SEQ ID NO 2038L6CAM135 GKAKPYQVRQVLRAVDKLETRRKKGGR 3234
PYPGWRLIKKILRVFKGL* 1619- SKRGRKRKDRRKKKANHGKRPNSGGGG 3235 CAM135
WRLIKKILRVFKGL* 1599-BD2.16 YSKTLHFADGGGKILKFLFKKVF* 3236
1619-BD2.16 SKRGRKRKDRRKKKANHGKRPNSGGG 3237 KILKFLFKKVF*
1904-BD2.16 GSVIKKRRKRMSKKKHRKMLRRTRVQR 3238
RKLGKGGGKILKFLFKKVF*
[0478] It was a surprising discovery that certain anti-S. mutans
STAMPs required a salt in the formulation (e.g., PBS) for optimum
activity. Thus, for example, the anti-S. mutans STAMP C16G2
(TFFRLFNRSFTQALGKGGGKNLRIIRKGIHIIKKY*, SEQ ID NO:2) comprising the
TFFRLFNRSFTQALGK (SEQ ID NO:1) attached to the antimicrobial
peptide (AMP) KNLRIIRKGIHIIKKY (SEQ ID NO: 3080) by a peptide
linker (GGG) was substantially inactive in water-based salt-free
buffers and nanoemulsions, but was active in a phosphate buffered
saline (PBS) formulation. Suitable PBS formulations ranged from
0.5.times.PBS to about 2.5.times.PBS with an activity optimum at
about 1.times.PBS. Similar results are believed to obtain for other
anti-S. mutans STAMPS as well as a number of other STAMPs. In
certain embodiments STAMP stability in solution was improved by
inclusion of fluoride in mouthrinse.
Example 5
Photodynamic Therapy Targeted Against Streptococcus mutans
[0479] Dental caries (tooth decay) is one of the most prevalent and
costly infectious diseases in the United States. Currently, the
annual expenditures on dental services exceed $85 billion, with the
majority of these costs attributable to dental caries and its
sequelae (www.ada.org/). The oral cavity harbors a complex
microbial community consisting of over 600 different
non-harmful/commensal microbial species together with a limited
number of pathogenic bacteria, including the major etiological
agent of dental caries, Streptococcus mutans. Once established, S.
mutans generates acid during the fermentation of dietary sugars,
which causes the demineralization of tooth structure and inhibits
the growth of non-pathogenic commensal bacteria within the same
microbial niche. Despite diligent use of broad-spectrum
antimicrobial compounds and tooth brushing, S. mutans persists
within the oral cavity and causes repeated cycles of cariogenesis.
Current "remove all, kill-all" approaches have shown limited
efficacy, since a "cleaned" tooth surface provides an equal
opportunity for commensal as well as pathogenic bacteria to
re-colonize in the non-sterile environment of the oral cavity. To
address this shortcoming, we have constructed and evaluated a
light-activated S. mutans-selective antimicrobial agent. C16-RB,
constructed via conjugation of the S. mutans competence-stimulating
peptide to the photodynamic dye rose bengal, displays robust
anti-S. mutans activity in vitro under blue exposure from a
handheld dental curing light. C16-RB has reduced activity against
other oral streptococci under mixed biofilm conditions and has
limited cytotoxicity in vitro.
[0480] To develop a method of selectively eliminating S. mutans
from a dental biofilm so that beneficial species exert a protective
colonization effect and long-term protection from S. mutans
re-colonization can be attained we created a novel class of
targeted antimicrobials, known as specifically-targeted
antimicrobial peptides, or STAMPs. STAMPs consist of functionally
independent, yet conjoined, domains within a linear peptide
sequence; a targeting region and an antimicrobial region. The
targeting region, which binds specifically to a bacterial species
of interest, delivers the killing portion of the molecule that
consists of a normally wide-spectrum antimicrobial peptide.
Previously, we successfully designed STAMPs against S. mutans by
taking advantage of the competence stimulating pheromone (CSP)
peptide produced by this organism that has demonstrated S.
mutans-specific recognition. STAMPs synthesized with portions of
CSP as targeting domains were capable of specific antimicrobial
activity against S. mutans, and not other oral streptococci or
non-cariogenic organisms in biofilms.
[0481] We hypothesized that targeted killing might be achieved
through the use of non-peptide antimicrobial molecules, such as
porphyrins or dyes utilized in PDT. Here we present the
proof-of-principle construction and in vitro efficacy of the
targeted, peptide-guided, photodynamic molecule C16-RB. C16-RB
displays S. mutans selective antimicrobial activity upon blue light
activation with limited activity against non-cariogenic oral
streptococci and epithelial cells.
Materials and Methods
[0482] Synthesis of C16-RB
[0483] All amino acids, synthesis resins and reagents were peptide
synthesis grade
[0484] (Anaspec, San Jose, Calif.; Fisher Scientific). To construct
our C16-RB conjugate, conventional 9-fluorenylmethoxy carbonyl
(Fmoc) solid-phase methodology was employed to synthesize the
CSP.sub.C16 peptide and attach the succinate and PEG linkers,
utilizing double coupling cycles in N-hydroxybenzotriazole, HBTU
(O-benzotriazole-N,N,N,N-tetramethyl-uronium hexafluoro-phosphate)
and diisopropyl ethylamine (DIEA), with dimethylformamide (DMF) and
N-methylpyrrolidone (NMP) as solvents, as described previously. The
peptide resin (1 molar equivalent, 15 mg) was then swollen in DMF
for 30 min prior to attachment of the PEG terminal amide group to
the carboxyl lactone in RB (FIG. 19B). This reaction was carried
out in a mixture of
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU, 5-molar excess) in dichloromethane
(DCM):DMF:dimethylsulphoxide (DMSO) (1:1:1 (v/v)). Ten molar
equivalents of DIEA were added to the reaction flask to initiate
the reaction, which was protected with argon and stirred at room
temperature for 5 h. After completion, the reaction mixture was
passed down sintered glass filtered vial and extensively washed
with DMF and DCM to remove all waste reagents. The resin was then
dried overnight in vacuum, and cleaved with 1 mL of trifluoroacetic
acid (TFA)/thioanisole/water/EDT (10/0.5/0.5/025) for 2 hr at room
temperature. The cleavage solution was precipitated with 10 mL
methyl-tert butyl ether, and the precipitate was washed twice with
the same amount of ether. The crude product was purified via
preparative-level HPLC (Source 15RPC column, ACTA purifier,
Amersham) and eluted with gradient acetonitrile/water from 10 to
35% in 10 min, which was increased to 90% over 8 min before finally
being washed 15 min with 95% acetonitrile.
[0485] C16-RB was purified further to >90% and the molecular
mass confirmed via LC/MS, utilizing increasing hydrophobicity
gradient of acetonitrile in water with 0.01% TFA as described above
(Waters X-bridge BEH 130 C18 column, 4.6.times.100 mm, particle
size 5 .mu.m, Waters 3100 system). LC spectra were analyzed with
MassLynx Softward v. 4.1 (Waters). C16-RB mass (3118.0) was
confirmed by electrospray ionization (ESI) mass spectroscopy in
linear, positive ion mode. The final product was lyophilized and
protected from light at all times. C16-RB was soluble in 50%
methanol.
[0486] Bacterial and Cellular Growth
[0487] Streptococcus oralis ATCC 10557, Streptococcus gordonii
(Challis), Streptococcus sanguinis (NY101), Streptococcus mitis
ATCC 903, Streptococcus salivarius ATCC 13419 and S. mutans
wild-type UA140 and JM11 (spectinomycin-resistant) strains were
grown in Todd-Hewitt (TH) broth 37.degree. C. in an anaerobic
atmosphere of 80% N.sub.2, 10% CO.sub.2, and 10% H.sub.2. BHK-21
(ATCC CRL-10) fibroblasts were propagated in DMEM with 10% FBS, 1
mM sodium pyruvate, 100 units/mL penicillin G, and 100 .mu.g/mL
streptomycin at 37.degree. C. with 5% CO.sub.2. Cells were detached
with 0.25% trypsin and subcultured as recommended by the
supplier.
[0488] Photodynamic Antimicrobial Assays Against Biofilms
[0489] To evaluate C16-RB against monoculture biofilms, S. mutans
UA140 was grown overnight in TH prior to inoculation for biofilm
formation. For biofilms, 1:5000 dilution of overnight culture was
made into TH with 1% sucrose in 2 mL centrifuge tubes (200 .mu.L
volume) and grown 24 h under anaerobic conditions. After
incubation, biofilms were treated for 5 min with 5 or 25 .mu.M
C16-RB or 5 .mu.M RB in 1.times.PBS, or PBS alone, followed by
removal of supernatant and exposure to 5 min blue light (emission
400-550 nm, power 400 mW/cm.sup.2) from an Astralis 7 (Ivoclar
Vivodent, Austria) handheld LED commonly used as a dental curing
light. The light source was suspended 4 cm from the tube bottom
(even with the mouth of the tube). A duplicate set of samples were
left covered to serve as dark controls. After treatment, biofilms
were mechanically disrupted and plated to determine cfu/mL.
[0490] To gauge C16-RB selectivity for S. mutans, similar assays
were conducted against multispecies biofilms. Mixed biofilms were
seeded by diluting (1:5000) a mixture of equal parts S. oralis, S.
gordonii, S. mitis, S. sanguinis, S. salivarius, and S. mutans JM11
(made from overnight cultures) into TH with 1% sucrose, 1% glucose,
and 1% mannose. Biofilms were incubated and treated as described
above with the addition of vitamin C or potassium gluconate. After
the addition of agent and 5 min incubation, biofilms were washed
1.times. with 1.times.PBS prior to light exposure. After PDT and
biofilm disruption, survivors were plated on TH, and TH
supplemented with 800 .mu.g/mL spectinomycin, which allowed for
quantitation of surviving total oral streptococci and surviving S.
mutans, respectively.
[0491] Evaluation of C16-RB Cytotoxicity
[0492] The effect of RB and C16-RB on human fibroblasts was
ascertained by utilizing the Promega CellTiterGlo assay, as
described by the manufacturer. Briefly, fibroblasts were grown to
confluence, detached, and seeded to 5,000 cells per well in a
96-well opaque walled, clear bottom 96-well plate (Nunc
International). For long-term dark toxicity, cells were allowed to
attach to for 18 h before the culture medium was replaced with
medium plus serially-diluted RB or C16-RB (200 .mu.M to 390 nM) or
medium alone. After 18-24 h, equal volume Cell Titer Glo reagent
was added to each well and mixed. Luciferace activity was then
quantified to measure cell viability (Varian Fluorometer in
Biolumenescence mode). To measure cytotoxicity after RB or C16-RB
light exposure, cells were seeded at .about.10,000 cells per well
and allowed to attach for 4 h. Cell growth medium was then replaced
with RB or C16-RB containing medium, prior to exposure (a single
well at a time) with blue light (400 mW/cm.sup.2) suspended
.about.3 cm from the well bottom. After exposure, cultures were
disrupted with Cell Titer Glo and luciferase activity quantitated
as above.
Results
[0493] Design of Photodynamic Peptide-Dye Conjugate
[0494] For the targeting peptide component of the chimeric
molecule, we selected a shortened derivative of S. mutans CSP,
CSP.sub.C16 (sequence: TFFRLFNRSFTQALGK). CSP.sub.C16 has been
utilized successfully as a STAMP targeting peptide in several
constructs, and demonstrates selective binding to S. mutans and not
other non-cariogenic bacteria. For the photodynamic dye, we
selected rose bengal (RB, FIG. 19A), a xanthene dye with a
demonstrated record of safety as a diagnostic tool in optometry.
Unlike TBO or methylene blue, RB is not recognized by efflux pumps,
and has shown robust activity against a variety of bacteria in
vitro in the presence of green or blue light (max absorption
.about.549 nm), and can be activated by a handheld dental curing
LED.
[0495] C16-RB Synthesis
[0496] As shown in FIG. 19B, RB was attached to the N-terminus of
CSP.sub.C16 through a succinate/PEG linker to construct the C16-RB
molecule. Conventional solid-phase peptide methods were utilized to
synthesize CSPC.sub.16, followed by linker and RB coupling prior to
cleavage from the resin. After cleavage, C16-RB was repeatedly
purified by LC/MS prior to evaluation. As shown in FIG. 20, over
95% purity was achieved with the expected mass species observed.
The lactone ring in RB was opened as a result of CSP.sub.C16
attachment. However, we hypothesized that the conjugate would
retain enough singlet-oxygen generating activity for a
proof-of-principle demonstration, as other xanthene dyes with
activity lack this ring.
[0497] C16-RB Efficacy Against Single-Species S. mutans
Biofilms
[0498] After synthesis, the basic photosensitization potential of
C16-RB was assessed by challenging mature single-species S. mutans
biofilms (grown 24 h) with C16-RB or unmodified RB, followed by
blue emission from a dental curing light. As shown in FIG. 21,
potent antimicrobial activity was observed in cultures exposed to
C16-RB or RB and blue light: a reduction in over 3 log.sub.10 from
input cfu/mL at 5 or 25 .mu.M. In contrast, appreciable decreases
in cfu/mL were not observed in S. mutans treated with blue light
alone, or 5 .mu.M RB or C16-RB dark controls. Modest dark toxicity
was observed in samples treated with 25 .mu.M C16-RB. Overall,
these results indicate that the peptide-dye conjugate is active
against S. mutans and at roughly similar levels to the parental RB
molecule.
[0499] Selective PDT Against Multi-Species Biofilms
[0500] C16-RB was next evaluated for selectivity in mixed cultures
containing S. mutans and non-cariogenic oral streptococci that
compete for the same niche on the tooth surface. We utilized mixed
biofilms of S. mutans transformed with spectinomycin resistance
(strain JM11, Merritt, et al., 2005), plus S. oralis, S. gordonii,
S. mitis, S. sanguinis, and S. salivarius. The mixed cultures were
grown 24 and then treated with RB or C16-RB as indicated, plus
potassium gluconate to minimize killing of untargeted bacteria by
reducing the superoxide-producing activity of the free C16-RB not
bound to S. mutans. Ethanol treatment served as an indiscriminant
killing control. As shown in FIG. 21, RB alone exhibited strong
indiscriminant photodynamic antimicrobial effects against S. mutans
and non-S. mutans in the mixed biofilm system (ratio of surviving
S. mutans:non-cariogenic streptococci cfu .about.1). In contrast,
C16-RB displayed specific photodynamic activity towards S. mutans,
and not the other oral streptococci examined, as reflected in the
low ratio of recovered S. mutans to other streptococci. These
results suggest C16-RB has antimicrobial activity in the presence
of blue light that is specific for S. mutans and dependent on the
CSP.sub.C16 targeting peptide.
[0501] Cytotoxicity Against Eukaryotic Cells
[0502] Given the demonstrated PDT potential of RB-C16, experiments
were conducted to examine the cytotoxicity for this conjugate and
RB alone. IC.sub.50s were obtained for BHK cells exposed C16-RB,
RB, or Melittin B (positive control for cytotoxicity), with and
without blue light exposure. As shown in Table 23, cytotoxicity was
noted for cells exposed to Melittin B at the lowest peptide
dilution tested at either 5 min or 24 h, with or without light
(IC.sub.50<1.56 .mu.M), while light-dependent toxicity was
observed only for RB-treated samples. No photo-associated toxicity
was noted in BHK cells treated with C16-RB, though modest
light-independent cytotoxicity (IC.sub.50=90 .mu.M) was detected
after 24 h of exposure. These results suggest that C16-RB is not
toxic to BHK cells after illumination, and displays mild toxic
effects (when compared to Melittin B) after 24 h exposure.
TABLE-US-00023 TABLE 23 Cytotoxicity of RB and C16-RB compounds.
IC.sub.50 (.mu.M) BHK 5 min dark: RB-C16 >100 RB >100
Melittin B <1.56 5 min w/blue light: RB-C16 >100 RB 40
Melittin B <1.56 24 h dark RB-C16 55 RB 90 Melittin B
<1.56
[0503] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20110039763A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20110039763A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References