U.S. patent application number 15/713352 was filed with the patent office on 2018-05-17 for minocycline compounds for biodefense.
The applicant listed for this patent is Paratek Pharmaceuticals, Inc.. Invention is credited to Michael P. Draper, S. Ken Tanaka.
Application Number | 20180133231 15/713352 |
Document ID | / |
Family ID | 56977663 |
Filed Date | 2018-05-17 |
United States Patent
Application |
20180133231 |
Kind Code |
A1 |
Draper; Michael P. ; et
al. |
May 17, 2018 |
MINOCYCLINE COMPOUNDS FOR BIODEFENSE
Abstract
Methods of treating or preventing a bacterial infection in a
subject are disclosed herein, wherein the bacterial infection is
caused by a bacterium which can be used as a biological weapon.
Also disclosed is a pharmaceutical composition comprising the
compound of the present invention for treating or preventing a
bacterial infection in a subject, wherein the bacterial infection
is caused by a bacterium which can be used as a biological
weapon.
Inventors: |
Draper; Michael P.;
(Windham, NH) ; Tanaka; S. Ken; (Bellevue,
WA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
Paratek Pharmaceuticals, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
56977663 |
Appl. No.: |
15/713352 |
Filed: |
September 22, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/US2016/023807 |
Mar 23, 2016 |
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15713352 |
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62137719 |
Mar 24, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61K 9/0019 20130101; A61K 31/65 20130101; A61P 31/04 20180101;
Y02A 50/30 20180101; Y02A 50/475 20180101 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61P 31/04 20060101 A61P031/04; A61K 9/00 20060101
A61K009/00 |
Claims
1. A method of treating a bacterial infection in a subject in need
thereof, said method comprising administering to said subject an
effective amount of a compound, or a salt thereof, at a dose of
about 10 mg to about 1000 mg, wherein the compound is Compound A'
of the following structural formula: ##STR00019## wherein said
bacterial infection is caused by a bacterium which can be used as a
biological weapon, such that said infection in said subject is
treated.
2. The method of claim 1, wherein the compound is Compound A of the
following structural formula: ##STR00020##
3. The method of claim 1, wherein the bacterium is resistant to
antibiotics that are typically used to treat infections caused by
the bacterium.
4. The method of claim 1, wherein the bacterium is in the form of a
powder or an aerosol.
5. The method of claim 1, wherein the bacterium is able to form
spores.
6. The method of claim 1, wherein the bacterium is selected from
the group comprising: a bacterium belonging to the species
Franciscella tularensis, Clostridium botulinum, Yersinia pestis,
Burkholderia mallei, Burkholderia pseudomallei, Coxiella burnetii,
Chlamydia psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes; a bacterium belonging to the genus Bacillus (e.g.,
B. anthracis, including Multi-Drug Resistant (MDR) anthrax
strains), Brucella (e.g., B. abortus, B. canis, B. ceti, B.
inopinata, B. melitensis, B. microti, B. neotomae, B. ovis, B.
pinnipedialis, B. suis), Shigella (e.g., S. boydii, S. dysenteriae,
S. flexneri and S. sonnei), Vibrio (e.g., V. cholerae), Salmonella
(e.g., S. bongori and S. enterica); and a bacterium belonging to a
diarrheagenic strain of E. coli.
7. The method of claim 6, wherein the bacterium is selected from
the group comprising: a bacterium belonging to the species
Franciscella tularensis, Yersinia pestis, Burkholderia mallei,
Burkholderia pseudomallei, Rickettsia prowazekii; and a bacterium
belonging to the genus Bacillus (e.g., B. anthracis, including
Multi-Drug Resistant (MDR) anthrax strains).
8. The method of claim 1, wherein the bacterium is selected from
the group consisting of: a bacterium belonging to the species
Franciscella tularensis, Clostridium botulinum, Yersinia pestis,
Burkholderia mallei, Burkholderia pseudomallei, Coxiella burnetii,
Chlamydia psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes; a bacterium belonging to the genus Bacillus (e.g.,
B. anthracis, including Multi-Drug Resistant (MDR) anthrax
strains), Brucella (e.g., B. abortus, B. canis, B. ceti, B.
inopinata, B. melitensis, B. microti, B. neotomae, B. ovis, B.
pinnipedialis, B. suis), Shigella (e.g., S. boydii, S. dysenteriae,
S. flexneri and S. sonnei), Vibrio (e.g., V. cholerae), Salmonella
(e.g., S. bongori and S. enterica); and a bacterium belonging to a
diarrheagenic strain of E. coli.
9. The method of claim 8, wherein the bacterium is selected from
the group consisting of: a bacterium belonging to the species
Franciscella tularensis, Yersinia pestis, Burkholderia mallei,
Burkholderia pseudomallei, Rickettsia prowazekii; and a bacterium
belonging to the genus Bacillus (e.g., B. anthracis, including
Multi-Drug Resistant (MDR) anthrax strains).
10. The method of claim 1, wherein the bacterium is selected from
the group consisting of: Yersinia pestis, Burkholderia mallei and
Bacillus anthracis.
11. The method of claim 1, wherein the compound is administered
once per day or twice per day.
12. The method of claim 1, wherein the compound is administered
intravenously or orally.
13. The method of claim 1, wherein the compound is administered
intravenously at the dose of about 50 mg to about 200 mg.
14. (canceled)
15. The method of claim 1, wherein the compound is administered
orally at the dose of about 100 to about 300 mg.
16. (canceled)
17. The method of claim 1, wherein the method comprises
administering the compound for at least 3 days, at least 7 days, at
least 14 days, at least 21 days, at least 30 days or at least 60
days.
18. (canceled)
19. The method of claim 1, wherein the method comprises
administering to the subject one or more loading doses of the
compound, followed by one or more maintenance doses of the
compound.
20. The method of claim 19, wherein the one or more loading dose is
greater than the one or more maintenance dose.
21. The method of claim 19, wherein the loading dose is intravenous
and the maintenance dose is oral.
22. The method of claim 1, wherein the subject is a human.
23. A method of preventing a bacterial infection in a subject in
need thereof, said method comprising administering to said subject
an effective amount of a compound, or a salt thereof, at a dose of
about 10 mg to about 1000 mg, wherein the compound is Compound A'
of the following structural formula: ##STR00021## wherein said
bacterial infection is caused by a bacterium which can be used as a
biological weapon, such that said infection in said subject is
prevented.
24-44. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation application of
International Patent Application No. PCT/US2016/023807, filed on
Mar. 23, 2016 and published as WO2016/154332; which claims priority
to U.S. Provisional Application No. 62/137,719, filed on Mar. 24,
2015. The entire contents of each of the foregoing applications are
hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Biological agents, including various types of bacteria such
as Bacillus anthracis and Multi Drug Resistant (MDR) anthracis,
Franciscella tularensis, Yersinia pestis, Burkholderia mallei,
Burkholderia pseudomallei, and Rickettsia prowazekii, can be used
as weapons, which pose a material threat to the national security
and public health in the United States. Tetracyclines have proven
clinical utilities as anti-bacterial agents. As a family they have
a well-established record of safety and efficacy. Tetracyclines
exert their anti-bacterial effects through multiple routes,
including binding to the 30S subunit of the bacterial ribosome and
inhibiting the binding of aminoacyl-tRNA. Tetracyclines are known
to be active against infections caused by various pathogens. In
many cases tetracyclines are indicated for treatment and
prophylaxis of diseases caused by these pathogens.
[0003] The most prevalent mechanisms of tetracycline resistance
among gram-positive and gram-negative bacteria are ribosome
protection and efflux. Both mechanisms are readily transferrable
among bacterial types as they are often associated with
transmissible genetic elements including plasmids, transposons, and
integrons, and have been shown to already occur. Therefore, there
is a need for effective anti-bacterial agents for the prevention,
prophylaxis, and treatment of infections caused by biological
agents, including those that can be used as weapons.
SUMMARY OF THE INVENTION
[0004] In some embodiments, the present invention provides a method
of treating a bacterial infection in a subject in need thereof, the
method comprising administering to the subject an effective amount
of a compound, or a salt thereof, at a dose of about 10 mg to about
1000 mg, wherein the compound is Compound A' of the following
structural formula:
##STR00001##
wherein the bacterial infection is caused by a bacterium which can
be used as a biological weapon, such that the infection in the
subject is treated.
[0005] In one embodiment, the compound is Compound A of the
following structural formula:
##STR00002##
[0006] In some aspects, the bacterium is resistant to antibiotics
that are typically used to treat infections caused by the
bacterium. In a specific aspect, the bacterium is in the form of a
powder or an aerosol. In another specific aspect, the bacterium is
able to form spores. In some embodiments, the bacterium may be
disseminated as spores, or via contamination of food or water
supply.
[0007] In one embodiment, the bacterium is selected from the group
comprising:
[0008] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0009] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae), Salmonella (e.g., S.
bongori and S. enterica); and
[0010] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0011] In another embodiment, the bacterium is selected from the
group comprising:
[0012] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0013] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0014] In some embodiments, the bacterium is selected from the
group consisting of:
[0015] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0016] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae), Salmonella (e.g., S.
bongori and S. enterica); and [0017] a bacterium belonging to a
diarrheagenic strain of E. coli.
[0018] In yet another embodiment, the bacterium is selected from
the group consisting of:
[0019] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0020] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0021] In yet another embodiment, the bacterium is selected from
the group consisting of: Yersinia pestis, Burkholderia mallei and
Bacillus anthracia.
[0022] In one embodiment, the compound is administered once per day
or twice per day.
[0023] In some embodiments, the compound is administered
intravenously or orally.
[0024] In an embodiment, the compound is administered intravenously
at the dose of about 50 mg to about 200 mg. In a further
embodiment, the compound is administered at the dose of about 100
mg.
[0025] In another embodiment, the compound is administered orally
at the dose of about 100 to about 300 mg.
[0026] In certain aspects, the method of the invention comprises
administering the compound, e.g., Compound A' or Compound A, for at
least 3 days, at least 7 days, at least 14 days, at least 21 days,
at least 30 days or at least 60 days. In a specific embodiment, the
method comprises administering the compound for about 30 days or
about 60 days.
[0027] In some embodiments, the method comprises administering to
the subject one or more loading doses of the compound, followed by
one or more maintenance doses of the compound. In one embodiment,
the one or more loading dose may be greater than the one or more
maintenance dose.
[0028] In a specific embodiment, the loading dose is an intravenous
dose and the maintenance dose is an oral dose. In another specific
embodiment, the loading dose is an intravenous dose and the
maintenance dose is also an intravenous dose. In yet another
specific embodiment, the loading dose is an oral dose and the
maintenance dose is also an oral dose.
[0029] In one embodiment, the subject is a human.
[0030] In some embodiments, the present invention also provides a
method of preventing a bacterial infection in a subject in need
thereof, the method comprising administering to the subject an
effective amount of a compound, or a salt thereof, at a dose of
about 10 mg to about 1000 mg, wherein the compound is Compound A'
of the following structural formula:
##STR00003##
wherein the bacterial infection is caused by a bacterium which can
be used as a biological weapon, such that the infection in the
subject is prevented.
[0031] In one embodiment, the compound is Compound A of the
following structural formula:
##STR00004##
[0032] In some aspects, the bacterium is resistant to antibiotics
that are typically used to treat infections caused by the
bacterium. In a specific aspect, the bacterium is in the form of a
powder or an aerosol. In another specific aspect, the bacterium is
able to form spores.
[0033] In one embodiment, the bacterium is selected from the group
comprising:
[0034] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0035] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae), Salmonella (e.g., S.
bongori and S. enterica); and
[0036] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0037] In another embodiment, the bacterium is selected from the
group comprising:
[0038] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0039] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0040] In some embodiments, the bacterium is selected from the
group consisting of:
[0041] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0042] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae), Salmonella (e.g., S.
bongori and S. enterica); and [0043] a bacterium belonging to a
diarrheagenic strain of E. coli.
[0044] In yet another embodiment, the bacterium is selected from
the group consisting of:
[0045] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0046] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0047] In yet another embodiment, the bacterium is selected from
the group consisting of: Yersinia pestis, Burkholderia mallei and
Bacillus anthracis.
[0048] In some aspects, the dose is about 50 mg to about 200 mg,
e.g., about 75 mg to about 110 mg. In one aspect, the dose is about
100 mg.
[0049] In one embodiment, the compound is administered once per day
or twice per day.
[0050] In another embodiment, the compound is administered
intravenously or orally.
[0051] In certain aspects, the method of the invention comprises
administering the compound, e.g., Compound A' or Compound A, for at
least 3 days, at least 7 days, at least 14 days, at least 21 days,
at least 30 days or at least 60 days. In a specific embodiment, the
method comprises administering the compound for about 30 days or
about 60 days.
[0052] In some embodiments, the method comprises administering to
the subject one or more loading doses of the compound, followed by
one or more maintenance doses of the compound. In one embodiment,
the one or more loading dose may be greater than the one or more
maintenance dose.
[0053] In a specific embodiment, the loading dose is an intravenous
dose and the maintenance dose is an oral dose. In another specific
embodiment, the loading dose is an intravenous dose and the
maintenance dose is also an intravenous dose. In yet another
specific embodiment, the loading dose is an oral dose and the
maintenance dose is also an oral dose.
[0054] In one embodiment, the subject is a human.
BRIEF DESCRIPTION OF THE DRAWINGS
[0055] FIG. 1 is a graph showing percent survival in a lethal Y.
pestis post-exposure prophylactic (PEP) mouse model after treatment
with Compound A (omadacycline), doxycycline and ciprofloxacin.
[0056] FIG. 2 is a graph showing percent survival in a B. anthracia
post-exposure prophylactic (PEP) mouse model after treatment with
Compound A (omadacycline), doxycycline or ciprofloxacin.
[0057] FIG. 3 is a graph showing percent survival in a lethal B.
mallei post-exposure prophylactic (PEP) mouse model after treatment
with Compound A (omadacycline), doxycycline or moxifloxacin.
DETAILED DESCRIPTION OF THE INVENTION
[0058] The invention relates to the discovery that
9-[(2,2-dimethyl-propyl amino)-methyl]minocycline (omadacycline,
OMC) is effective to treat or prevent infections caused by various
types of bacteria that can be used as biological weapons.
[0059] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A' or a salt thereof:
##STR00005##
[0060] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject a compound or a salt
thereof, at a dose of about 10 mg to about 1000 mg, wherein the
compound is Compound A' of the following structural formula:
##STR00006##
[0061] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A' or a salt thereof:
##STR00007##
[0062] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject a compound or a salt
thereof, at a dose of about 10 mg to about 1000 mg, wherein the
compound is Compound A' of the following structural formula:
##STR00008##
[0063] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A or a salt thereof:
##STR00009##
[0064] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject a compound or a salt
thereof, at a dose of about 10 mg to about 1000 mg, wherein the
compound is Compound A of the following structural formula:
##STR00010##
[0065] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A or a salt thereof:
##STR00011##
[0066] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject a compound or a salt
thereof, at a dose of about 10 mg to about 1000 mg, wherein the
compound is Compound A of the following structural formula:
##STR00012##
[0067] In a particular embodiment, the invention pertains, at least
in part, to a method of treating an infection in a subject or
preventing an infection in a subject, comprising administering to
the subject an effective amount of Compound A' or Compound A,
wherein the infection is caused by a bacterium which can be used as
a biological weapon.
[0068] In one embodiment, a bacterium which can be used as a
biological weapon includes a bacterium which possesses one or more
of the characteristics, including but not limited to, easily being
produced or disseminated, easily being transmitted from person to
person, having potential for moderate or high morbidity, having
potential for moderate or high mortality, having potential for
causing public panic and social disruption, requiring special
action for public health preparedness, and requiring specific
enhancements for diagnosis and disease surveillance.
[0069] In one embodiment, a bacterium which can be used as a
biological weapon is stable or viable (e.g., capable of performing
all or part of its normal biological functions, such as
replicating, forming spores, and infecting a subject) under various
conditions (e.g., heat, cold, high pressure, low pressure, acidic
or basic conditions, humidity, dryness, and radiation), including
extreme conditions. In one embodiment, a bacterium which can be
used as a biological weapon is capable of infecting a subject under
various conditions. In one embodiment, a bacterium which can be
used as a biological weapon is stable or viable under a temperature
above 25.degree. C., 30.degree. C., 40.degree. C., 50.degree. C.,
60.degree. C., 70.degree. C., 80.degree. C., 90.degree. C.,
100.degree. C., 125.degree. C., 150.degree. C., 175.degree. C., or
200.degree. C. In one embodiment, a bacterium which can be used as
a biological weapon is stable or viable under a temperature below
25.degree. C., 20.degree. C., 10.degree. C., 5.degree. C.,
0.degree. C., -10.degree. C., -20.degree. C., -30.degree. C.,
-40.degree. C., -50.degree. C., -60.degree. C., -70.degree. C.,
-100.degree. C., or -150.degree. C. In one embodiment, a bacterium
which can be used as a biological weapon is stable or viable under
a pressure above 5.times.10.sup.5 Pa, 10.times.10.sup.5 Pa,
15.times.10.sup.5 Pa, 20.times.10.sup.5 Pa, 30.times.10.sup.5 Pa,
40.times.10.sup.5 Pa, 50.times.10.sup.5 Pa, 75.times.10.sup.5 Pa,
or 100.times.10.sup.5 Pa. In one embodiment, a bacterium which can
be used as a biological weapon is stable or viable under a pressure
below 0.5.times.10.sup.5 Pa, 0.2.times.10.sup.5 Pa,
0.1.times.10.sup.5 Pa, 0.05.times.10.sup.5 Pa, 0.02.times.10.sup.5
Pa, 0.01.times.10.sup.5 Pa, 0.005.times.10.sup.5 Pa,
0.002.times.10.sup.5 Pa, or 0.001.times.10.sup.5 Pa. In one
embodiment, a bacterium which can be used as a biological weapon is
stable or viable under a pH above 8.0, 8.5, 9.0, 9.5, 10.0, 10.5,
11.0, 11.5, 12.0, 12.5, 13.0, 13.5, or 14.0. In one embodiment, a
bacterium which can be used as a biological weapon is stable or
viable under a pH below 6.0, 5.5, 5.0, 4.5, 4.0, 3.5, 3.0, 2.5,
2.0, 1.5, 1.0, 0.5, or 0.0. In one embodiment, a bacterium which
can be used as a biological weapon is stable or viable under a
relative humidity of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%,
85%, 90%, 95%, or 99%. In one embodiment, a bacterium which can be
used as a biological weapon is stable or viable under f UV
radiation, X-ray radiation, a radiation, 13 radiation, or y
radiation. In another embodiment, the bacterium is capable of
infecting a subject after being treated with a combination of any
of the aforementioned conditions.
[0070] In one embodiment, a bacterium which can be used as a
biological weapon is able to form spores.
[0071] In one embodiment, the bacterium which can be used as a
biological weapon may be disseminated as spores. In another
embodiment, the embodiment which can be used as a biological weapon
may be disseminated via contamination of food or water supply. In
yet another embodiment, the bacterium which can be used as a
biological weapon may be disseminated by insects (e.g., fleas, lice
and ticks) and/or rodents (e.g., mice or rats).
[0072] In one embodiment, a bacterium which can be used as a
biological weapon can be dispersed in air or in liquid. In one
embodiment, the bacterium is in a form of an aerosol (e.g., the
bacterium is formulated as an aerosol). In another embodiment, the
bacterium is in a form of powder (e.g., the bacterium is formulated
as powder).
[0073] In one embodiment, a bacterium which can be used as a
biological weapon includes a bacterium which is resistant to
existing antibiotics, i.e., antibiotics that are typically used to
treat infections caused by the bacterium. In one embodiment, such
antibiotics include, e.g., tetracycline antibiotics, including but
not limited to tetracycline, doxycycline, minocycline, sancycline,
methacycline, chlortetracycline, and deoxytetracycline, and a
combination thereof, and other antibiotics, including but not
limited to, methicillin, oxacillin, vancomycin, penicillin,
linezolid, ciprofloxacin, ceftazidime, and azithromycin. In a
further embodiment, a bacterium which can be used as a biological
weapon includes a bacterium which is resistant to tetracycline,
minocycline, and/or doxycycline.
[0074] In one embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0075] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0076] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0077] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0078] In another embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0079] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0080] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0081] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0082] In one embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0083] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0084] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V. vulnificus),
Salmonella (e.g., S. bongori and S. enterica); and a bacterium
belonging to a diarrheagenic strain of E. coli.
[0085] In another embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0086] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0087] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio genus (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and a
bacterium belonging to a diarrheagenic strain of E. coli.
[0088] In a further embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0089] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0090] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0091] In a further embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to:
[0092] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Rickettsia
prowazekii; and
[0093] a bacterium belonging to the Bacillus genus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0094] In a further embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, a bacterium
belonging to the species Franciscella tularensis, Yersinia pestis,
Burkholderia mallei, Burkholderia pseudomallei, and Rickettsia
prowazekii. In a further embodiment, a bacterium which can be used
as a biological weapon includes, but is not limited to, a bacterium
belonging to the species Franciscella tularensis, Yersinia pestis,
Burkholderia mallei, and Rickettsia prowazekii. In a further
embodiment, a bacterium which can be used as a biological weapon is
a bacterium belonging to the species Bacillus anthracis or a
bacterium belonging to a Multi-Drug Resistant (MDR) anthrax
strain.
[0095] The Bacillus genus comprises the species of Bacillus
anthracis (the etiologic agent of anthrax), Bacillus cereus,
Bacillus weihenstephanensis (a food borne pathogen), Bacillus
thuringiensis (an insect pathogen), and Bacillus mycoides.
[0096] In one embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, a bacterium of
the Bacillus cereus group (e.g., Bacillus anthracis and Multi-Drug
Resistant (MDR) anthracis), Franciscella tularensis, Clostridium
botulinum, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Brucella species, Shigella species, Coxiella
burnetii, Chlamydia psittaci, Clostridium perfringens, Rickettsia
prowazekii, Diarrheagenic E. coli, Pathogenic Vibrios, Salmonella,
Campylobacter jejuni, Yersinia enterocolitica, and Listeria
monocytogenes. In one embodiment, a bacterium which can be used as
a biological weapon includes, but is not limited to, a bacterium of
the Bacillus cereus group (e.g., Bacillus anthracis and Multi-Drug
Resistant (MDR) anthracis), Franciscella tularensis, Clostridium
botulinum, Yersinia pestis, Burkholderia mallei, Brucella species,
Shigella species, Coxiella burnetii, Chlamydia psittaci,
Clostridium perfringens, Rickettsia prowazekii, Diarrheagenic E.
coli, Pathogenic Vibrios, Salmonella, Campylobacter jejuni,
Yersinia enterocolitica, and Listeria monocytogenes.
[0097] In one embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Brucella species, Shigella
species, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Diarrheagenic E. coli,
Pathogenic Vibrios, Salmonella, Campylobacter jejuni, Yersinia
enterocolitica, and Listeria monocytogenes. In one embodiment, a
bacterium which can be used as a biological weapon includes, but is
not limited to, Franciscella tularensis, Clostridium botulinum,
Yersinia pestis, Burkholderia mallei, Brucella species, Shigella
species, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Diarrheagenic E. coli,
Pathogenic Vibrios, Salmonella, Campylobacter jejuni, Yersinia
enterocolitica, and Listeria monocytogenes.
[0098] In a further embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, a bacterium of
the Bacillus cereus group (e.g., Bacillus anthracis and MultiDrug
Resistant (MDR) anthracis), Franciscella tularensis, Yersinia
pestis, Burkholderia mallei, Burkholderia pseudomallei, and
Rickettsia prowazekii. In a further embodiment, a bacterium which
can be used as a biological weapon includes, but is not limited to,
a bacterium of the Bacillus cereus group (e.g., Bacillus anthracis
and Multi-Drug Resistant (MDR) anthracis), Franciscella tularensis,
Yersinia pestis, Burkholderia mallei, and Rickettsia
prowazekii.
[0099] In a further embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, and Rickettsia prowazekii. In a further embodiment, a
bacterium which can be used as a biological weapon includes, but is
not limited to, Franciscella tularensis, Yersinia pestis,
Burkholderia mallei, and Rickettsia prowazekii.
[0100] In a further embodiment, a bacterium which can be used as a
biological weapon is Bacillus anthracis or Multi-Drug Resistant
(MDR) anthracis.
[0101] Bacillus cereus group of bacteria is composed of Bacillus
anthracis (the etiologic agent of anthrax), Bacillus cereus, and
Bacillus weihenstephanensis (a food borne pathogen), Bacillus
thuringiensis (an insect pathogen), and Bacillus mycoides.
[0102] In one embodiment, a bacterium which can be used as a
biological weapon does not belong to the species B. anthracis, Y.
pestis, F. tularensis, B. mallei or B. pseudomallei. In a specific
embodiment, a bacterium which can be used as a biological weapon
does not belong to the species B. anthracis. In another embodiment,
a bacterium which can be used as a biological weapon does not
belong to the species Y. pestis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species F. tularensis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. mallei. In yet another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. pseudomallei.
[0103] In one embodiment, a bacterium which can be used as a
biological weapon is not a bacterium that may be a causative agent
of a food borne disease. In a specific embodiment, a bacterium
which can be used as a biological weapon does not belong to a
diarrheagenic strain of E. coli. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the genus Salmonella (e.g., S. bongori and S. enterica). In yet
another specific embodiment, a bacterium which can be used as a
biological weapon does not belong to the species Campylobacter
jejuni.
[0104] In another embodiment, a bacterium which can be used as a
biological weapon is a bacterium that may be a causative agent of a
food borne disease. In a specific embodiment, a bacterium which can
be used as a biological weapon belongs to a diarrheagenic strain of
E. coli. In another specific embodiment, a bacterium which can be
used as a biological weapon belongs to the genus Salmonella (e.g.,
S. bongori and S. enterica). In yet another specific embodiment, a
bacterium which can be used as a biological weapon belongs to the
species Campylobacter jejuni.
[0105] A "food borne disease" or a "food borne illness", or "food
poisoning" is any illness resulting from the consumption of food
contaminated with, e.g., bacteria. In certain embodiments, the
contaminating bacteria may cause an infection and irritation of the
gastrointestinal tract. In some embodiments, the contaminating
bacteria may belong to a diarrheagenic strain of E. coli; to the
species Campylobacter jejuni; or to the genus Salmonella (e.g., S.
bongori or S. enterica).
[0106] In one embodiment, a bacterium which can be used as a
biological weapon includes, but is not limited to, gram-positive
pathogens, gram-negative pathogens, anaerobic pathogens, or
atypical pathogens, or a combination thereof. In a further
embodiment, a bacterium which can be used as a biological weapon
includes, but not limited to, a bacterium belonging to the species
methicillin-susceptible Staphylococcus aureus (MSSA),
methicillin-resistant Staphylococcus aureus (MRSA), oxacillin
susceptible Staphylococcus aureus, oxacillin-resistant
Staphylococcus aureus, oxacillin-resistant coagulase-negative
Staphylococcus, Enterococcus faecalis, Enterococcus faecium,
vancomycin susceptible Enterococcus faecium, vancomycin-resistant
Enterococcus faecium, vancomycin susceptible Enterococcus faecalis,
vancomycin-resistant Enterococcus faecalis, Streptococcus
pneumoniae, penicillin-susceptible Streptococcus pneumoniae,
penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcus
pyogenes, Streptococcus agalactiae, Haemophilus influenzae,
Moraxella catarrhalis, Neisseria gonorrhoeae, Escherichia coli,
Shigella spp., Salmonella spp., Klebsiella pneumoniae, Enterobacter
aerogenes, Enterobacter cloacae, Serratia marcescens, Acinetobacter
baumannii, Stenotrophomonas maltophilia, Bacteroides fragilis,
Clostridium perfringens, Chlamydia pneumoniae, Legionella
pneumophila, Proteus mirabilis, Pseudomonas aeruginosa, and
Burkholderia cepacia.
[0107] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A' or a salt thereof:
##STR00013##
wherein the bacterial infection is caused by a bacterium selected
from the group consisting of:
[0108] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0109] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0110] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0111] In another embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0112] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0113] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0114] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0115] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0116] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0117] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V. vulnificus),
Salmonella (e.g., S. bongori and S. enterica); and
[0118] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0119] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0120] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0121] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio genus (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0122] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0123] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0124] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0125] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0126] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0127] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Rickettsia
prowazekii; and
[0128] a bacterium belonging to the Bacillus genus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0129] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of a
bacterium belonging to the species Franciscella tularensis,
Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei,
and Rickettsia prowazekii. In a further embodiment, a bacterium
which can be used as a biological weapon is selected from the group
consisting of a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, and Rickettsia
prowazekii. In another embodiment, a bacterium which can be used as
a biological weapon is a bacterium belonging to the species
Bacillus anthracis or a bacterium belonging to a Multi-Drug
Resistant (MDR) anthrax strain.
[0130] In one embodiment, a bacterium which can be used as a
biological weapon does not belong to the species B. anthracis, Y.
pestis, F. tularensis, B. mallei or B. pseudomallei. In a specific
embodiment, a bacterium which can be used as a biological weapon
does not belong to the species B. anthracis. In another embodiment,
a bacterium which can be used as a biological weapon does not
belong to the species Y. pestis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species F. tularensis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. mallei. In yet another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. pseudomallei.
[0131] In one embodiment, a bacterium which can be used as a
biological weapon is not a bacterium that may be a causative agent
of a food borne disease. In a specific embodiment, a bacterium
which can be used as a biological weapon does not belong to a
diarrheagenic strain of E. coli. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the genus Salmonella (e.g., S. bongori and S. enterica). In yet
another specific embodiment, a bacterium which can be used as a
biological weapon does not belong to the species Campylobacter
jejuni.
[0132] It will be understood that for all listed embodiments the
compound of the invention, e.g., Compound A', may be administered
at a dose of about 10 mg to about 1000 mg.
[0133] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A' or a salt thereof:
##STR00014##
wherein the bacterial infection is caused by a bacterium selected
from the group consisting of:
[0134] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0135] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0136] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0137] In another embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0138] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0139] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0140] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0141] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0142] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0143] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V. vulnificus),
Salmonella (e.g., S. bongori and S. enterica); and
[0144] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0145] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0146] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0147] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio genus (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0148] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0149] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0150] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0151] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0152] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0153] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Rickettsia
prowazekii; and
[0154] a bacterium belonging to the Bacillus genus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0155] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of a
bacterium belonging to the species Franciscella tularensis,
Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei,
and Rickettsia prowazekii. In a further embodiment, a bacterium
which can be used as a biological weapon is selected from the group
consisting of a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, and Rickettsia
prowazekii. In another embodiment, a bacterium which can be used as
a biological weapon is a bacterium belonging to the species
Bacillus anthracis or a bacterium belonging to a Multi-Drug
Resistant (MDR) anthrax strain.
[0156] In one embodiment, a bacterium which can be used as a
biological weapon does not belong to the species B. anthracis, Y.
pestis, F. tularensis, B. mallei or B. pseudomallei. In a specific
embodiment, a bacterium which can be used as a biological weapon
does not belong to the species B. anthracis. In another embodiment,
a bacterium which can be used as a biological weapon does not
belong to the species Y. pestis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species F. tularensis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. mallei. In yet another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. pseudomallei.
[0157] In one embodiment, a bacterium which can be used as a
biological weapon is not a bacterium that may be a causative agent
of a food borne disease. In a specific embodiment, a bacterium
which can be used as a biological weapon does not belong to a
diarrheagenic strain of E. coli. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the genus Salmonella (e.g., S. bongori and S. enterica). In yet
another specific embodiment, a bacterium which can be used as a
biological weapon does not belong to the species Campylobacter
jejuni.
[0158] It will be understood that for all listed embodiments the
compound of the invention, e.g., Compound A' may be administered at
a dose of about 10 mg to about 1000 mg.
[0159] In one embodiment, the invention pertains, at least in part,
to a method of treating a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A or a salt thereof:
##STR00015##
wherein the bacterial infection is caused by a bacterium selected
from the group consisting of:
[0160] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0161] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0162] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0163] In another embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0164] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0165] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0166] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0167] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0168] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0169] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V. vulnificus),
Salmonella (e.g., S. bongori and S. enterica); and
[0170] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0171] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0172] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0173] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio genus (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0174] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0175] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0176] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0177] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax
strains).
[0178] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0179] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Rickettsia
prowazekii; and
[0180] a bacterium belonging to the Bacillus genus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0181] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of a
bacterium belonging to the species Franciscella tularensis,
Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei,
and Rickettsia prowazekii. In a further embodiment, a bacterium
which can be used as a biological weapon is selected from the group
consisting of a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, and Rickettsia
prowazekii. In another embodiment, a bacterium which can be used as
a biological weapon is a bacterium belonging to the species
Bacillus anthracis or a bacterium belonging to a Multi-Drug
Resistant (MDR) anthrax strain.
[0182] In one embodiment, a bacterium which can be used as a
biological weapon does not belong to the species B. anthracis, Y.
pestis, F. tularensis, B. mallei or B. pseudomallei. In a specific
embodiment, a bacterium which can be used as a biological weapon
does not belong to the species B. anthracis. In another embodiment,
a bacterium which can be used as a biological weapon does not
belong to the species Y. pestis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species F. tularensis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. mallei. In yet another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. pseudomallei.
[0183] In one embodiment, a bacterium which can be used as a
biological weapon is not a bacterium that may be a causative agent
of a food borne disease. In a specific embodiment, a bacterium
which can be used as a biological weapon does not belong to a
diarrheagenic strain of E. coli. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the genus Salmonella (e.g., S. bongori and S. enterica). In yet
another specific embodiment, a bacterium which can be used as a
biological weapon does not belong to the species Campylobacter
jejuni.
[0184] It will be understood that for all listed embodiments the
compound of the invention, e.g., Compound A, may be administered at
a dose of about 10 mg to about 1000 mg.
[0185] In one embodiment, the invention pertains, at least in part,
to a method of preventing a bacterial infection in a subject,
comprising administering to the subject an effective amount of
Compound A or a salt thereof:
##STR00016##
wherein the bacterial infection is caused by a bacterium selected
from the group consisting of:
[0186] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0187] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0188] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0189] In another embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0190] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0191] a bacterium belonging to the genus Bacillus (e.g., B.
anthracia, including Multi-Drug Resistant (MDR) anthrax strains),
Brucella (e.g., B. abortus, B. canis, B. ceti, B. inopinata, B.
melitensis, B. microti, B. neotomae, B. ovis, B. pinnipedialis, B.
suis), Shigella (e.g., S. boydii, S. dysenteriae, S. flexneri and
S. sonnei), Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0192] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0193] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0194] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Burkholderia pseudomallei, Coxiella burnetii, Chlamydia
psittaci, Clostridium perfringens, Rickettsia prowazekii,
Campylobacter jejuni, Yersinia enterocolitica, Listeria
monocytogenes;
[0195] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio (e.g., V. cholerae, V. parahaemolyticus, and V. vulnificus),
Salmonella (e.g., S. bongori and S. enterica); and
[0196] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0197] In one embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0198] a bacterium belonging to the species Franciscella
tularensis, Clostridium botulinum, Yersinia pestis, Burkholderia
mallei, Coxiella burnetii, Chlamydia psittaci, Clostridium
perfringens, Rickettsia prowazekii, Campylobacter jejuni, Yersinia
enterocolitica, Listeria monocytogenes;
[0199] a bacterium belonging to the genus Brucella (e.g., B.
abortus, B. canis, B. ceti, B. inopinata, B. melitensis, B.
microti, B. neotomae, B. ovis, B. pinnipedialis, B. suis), Shigella
(e.g., S. boydii, S. dysenteriae, S. flexneri and S. sonnei),
Vibrio genus (e.g., V. cholerae, V. parahaemolyticus, and V.
vulnificus), Salmonella (e.g., S. bongori and S. enterica); and
[0200] a bacterium belonging to a diarrheagenic strain of E.
coli.
[0201] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0202] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Burkholderia
pseudomallei, Rickettsia prowazekii; and
[0203] a bacterium belonging to the genus Bacillus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0204] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of:
[0205] a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, Rickettsia
prowazekii; and
[0206] a bacterium belonging to the Bacillus genus (e.g., B.
anthracis, including Multi-Drug Resistant (MDR) anthrax
strains).
[0207] In a further embodiment, a bacterium which can be used as a
biological weapon is selected from the group consisting of a
bacterium belonging to the species Franciscella tularensis,
Yersinia pestis, Burkholderia mallei, Burkholderia pseudomallei,
and Rickettsia prowazekii. In a further embodiment, a bacterium
which can be used as a biological weapon is selected from the group
consisting of a bacterium belonging to the species Franciscella
tularensis, Yersinia pestis, Burkholderia mallei, and Rickettsia
prowazekii. In another embodiment, a bacterium which can be used as
a biological weapon is a bacterium belonging to the species
Bacillus anthracis or a bacterium belonging to a Multi-Drug
Resistant (MDR) anthrax strain.
[0208] In one embodiment, a bacterium which can be used as a
biological weapon does not belong to the species B. anthracis, Y.
pestis, F. tularensis, B. mallei or B. pseudomallei. In a specific
embodiment, a bacterium which can be used as a biological weapon
does not belong to the species B. anthracis. In another embodiment,
a bacterium which can be used as a biological weapon does not
belong to the species Y. pestis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species F. tularensis. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. mallei. In yet another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the species B. pseudomallei.
[0209] In one embodiment, a bacterium which can be used as a
biological weapon is not a bacterium that may be a causative agent
of a food borne disease. In a specific embodiment, a bacterium
which can be used as a biological weapon does not belong to a
diarrheagenic strain of E. coli. In another specific embodiment, a
bacterium which can be used as a biological weapon does not belong
to the genus Salmonella (e.g., S. bongori and S. enterica). In yet
another specific embodiment, a bacterium which can be used as a
biological weapon does not belong to the species Campylobacter
jejuni.
[0210] It will be understood that for all listed embodiments the
compound of the invention, e.g., Compound A, may be administered at
a dose of about 10 mg to about 1000 mg.
[0211] In one embodiment, treating a bacterial infection in a
subject comprises administering the compound of the present
invention after the subject's exposure to the bacterium, but before
the subject develops a symptom of the bacterial infection. In one
embodiment, the compound of the present invention is administered
10 min, 20 min, 30 min, 40 min, 50 min, 1 hr, 2 hrs, 3 hrs, 6 hrs,
12 hrs, 18 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 96 hrs, 1 week, or
2 weeks after the subject's exposure but before the subject
develops a symptom of the bacterial infection.
[0212] In another embodiment, treating a bacterial infection in a
subject comprises administering the compound of the present
invention after the subject develops a symptom after the subject's
exposure to the bacterium. In one embodiment, the compound of the
present invention is administered 10 min, 20 min, 30 min, 40 min,
50 min, 1 hr, 2 hrs, 3 hrs, 6 hrs, 12 hrs, 18 hrs, 24 hrs, 36 hrs,
48 hrs, 72 hrs, 96 hrs, 1 week, or 2 weeks after the subject
develops a symptom of the bacterial infection.
[0213] In another embodiment, treating a bacterial infection in a
subject comprises administering the compound of the present
invention after the subject's suspected exposure to the bacterium,
but before the subject develops any symptom of the bacterial
infection. In one embodiment, the compound of the present invention
is administered 10 min, 20 min, 30 min, 40 min, 50 min, 1 hr, 2
hrs, 3 hrs, 6 hrs, 12 hrs, 18 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs,
96 hrs, 1 week, or 2 weeks after the subject's suspected exposure
but before the subject develops any symptom.
[0214] "Suspected exposure" means that there is certain possibility
(e.g., 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%,
95%, or 99%), although it is not known, that a subject has been
exposed to a bacterium and thus is at the risk of a bacterial
infection. In some embodiments, "suspected exposure" refers to a
chance of greater than 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%,
80%, 85%, 90%, 95%, or 99% that the subject has been exposed to a
bacterial and is therefore at a risk of a bacterial infection. For
example, "suspected exposure" means that there is greater than 50%
possibility that a subject has been exposed to a bacterium.
[0215] A "symptom" of a bacterial infection can be any indication
that the subject being exposed or suspected being exposed to the
bacterium is not normal, well, or comfortable, regardless of the
subject's subjective perception or feeling. "Symptom" includes, but
is not limited to, headache, stomachache, abdominal cramps,
abdominal pain, muscle pain, fever, diarrhea, vomiting, coughing,
weakness, tiredness, soreness, rash or bumps on skin, wounds in any
parts of the body (e.g., skin, head, eye, ear, nose, mouth, torso,
limbs, arm, hand, leg, foot, etc.), and an abnormality in any
tissue or organ (e.g., skin, bone, blood, lymph, intestine,
stomach, pancreas, brain, heart, lung, liver, spleen, kidney,
bladder, ovary, etc.).
[0216] In one embodiment, preventing a bacterial infection in a
subject comprises administering the compound of the present
invention before the subject's exposure to the bacterium. In one
embodiment, the compound of the present invention is administered
10 min, 20 min, 30 min, 40 min, 50 min, 1 hr, 2 hrs, 3 hrs, 6 hrs,
12 hrs, 18 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 96 hrs, 1 week, or
2 weeks before the subject's exposure. In another embodiment,
preventing a bacterial infection in a subject comprises
administering the compound of the present invention before or after
an event which raises the risk of the subject being exposed to the
bacterium. The event includes, but is not limited to, a terrorist
attack with a biological weapon and the subject's entry into a
risky territory, such as a battlefield. In one embodiment, the
compound of the present invention is administered to the subject 10
min, 20 min, 30 min, 40 min, 50 min, 1 hr, 2 hrs, 3 hrs, 6 hrs, 12
hrs, 18 hrs, 24 hrs, 36 hrs, 48 hrs, 72 hrs, 96 hrs, 1 week, or 2
weeks before the event. In another embodiment, the compound of the
present invention is administered to the subject 10 min, 20 min, 30
min, 40 min, 50 min, 1 hr, 2 hrs, 3 hrs, 6 hrs, 12 hrs, 18 hrs, 24
hrs, 36 hrs, 48 hrs, 72 hrs, 96 hrs, 1 week, or 2 weeks after the
event.
[0217] In one embodiment, the methods of the present application
may further comprise, before administering the compound of the
present invention, identifying a subject at risk of being exposed
to a bacterium which can be used as a biological weapon. The
subject at a risk of being exposed to a bacterium which can be used
as a biological weapon includes, but is not limited to, a subject
travelling to, entering, or being in a conflict region (e.g., a
battlefield and combat zone), such as military personnel,
intelligence personnel, and animals used in the military, a subject
engaged or about to be engaged in a security operation, such as
governmental authorities (e.g., police, governmental investigators,
and secret service members) and other personnel (e.g., doctors,
nurses, and rescue workers), and animals used in such an operation,
and a subject in an geographical area that is likely to be a target
of a terrorist attack (e.g., a metropolitan area, a city, an area
where there is a large population (e.g., above 100,000, above
200,000, above 500,000, above 1 million, above 2 million, above 5
million, and above 10 million), and a location or area a damage to
which is likely to cause a threat to national security or public
health (e.g., a nuclear power plant, a chemical plant, an airport,
and a hospital).
[0218] "Expose", "exposure", or "exposed" means that a subject
comes in contact in any way with a bacterium or any component
thereof (e.g., bacterial cell wall, bacterial cell membrane, a
bacterial nucleic acid, a bacterial polynucleotide, a bacterial
protein, a bacterial polypeptide, a bacterial spore, and a
bacterial toxin). For example, a subject may be exposed to a
bacterium or any component thereof by ingesting, inhaling, or
touching anything which contains the bacterium or any component
thereof. For example, the component of the bacterium is capable of
causing an infection or symptoms of an infection in the subject.
For example, the bacterial component is a bacterial spore.
[0219] In one embodiment, the invention pertains to a method of
treating a bacterial infection in a subject, wherein the subject is
exposed or suspected of being exposed to a bacterium or a component
thereof, comprising administering to the subject an effective
amount of Compound A' or Compound A, or a salt thereof. In another
embodiment, the invention also pertains to a method of treating a
bacterial infection in a subject, wherein the subject is exposed or
suspected of being exposed to a bacterium or a component thereof,
comprising administering to the subject Compound A' or Compound A,
or a salt thereof, at a dose of about 10 mg to about 1000 mg. In
one embodiment, the invention also pertains to a method of
preventing a bacterial infection in a subject, wherein the subject
is at a risk of being exposed to a bacterium or a component
thereof, comprising administering to the subject an effective
amount of a compound of Compound A' or Compound A, or a salt
thereof. In another embodiment, the invention also pertains to a
method of preventing a bacterial infection in a subject, wherein
the subject is at a risk of being exposed to a bacterium or a
component thereof, comprising administering to the subject an
effective amount of Compound A' or Compound A, or a salt thereof,
at a dose of about 10 mg to about 1000 mg. In one embodiment, the
bacterium or a component thereof is formulated as an aerosol or
power. In one embodiment, the bacterial component is a bacterial
spore.
[0220] A compound of the invention, e.g., Compound A, may be
administered to a subject by any mode of administration that can
achieve a level of Compound A in the subject that is effective to
treat or prevent an infection. In one embodiment, a compound of the
present invention is administered orally. In another embodiment, a
compound of the present invention is administered intravenously. In
another embodiment, a compound of the present invention is
administered intraperitoneally. In yet another embodiment, a
compound of the present invention is administered
subcutaneously.
[0221] In some embodiments, the compound of the invention may be
administered at a dose of 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5
mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12 mg/kg, 14
mg/kg, 16 mg/kg, 18 mg/kg, 20 mg/kg, 22 mg/kg, 24 mg/kg, 26 mg/kg,
28 mg/kg, 30 mg/kg, 32 mg/kg, 34 mg/kg, 36 mg/kg, 38 mg/kg, 40
mg/kg, 42 mg/kg, 44 mg/kg, 46 mg/kg, 48 mg/kg, 50 mg/kg, 52 mg/kg,
54 mg/kg, 56 mg/kg, 58 mg/kg, 60 mg/kg, 62 mg/kg, 64 mg/kg, 66
mg/kg, 68 mg/kg, 70 mg/kg, 72 mg/kg, 74 mg/kg, 76 mg/kg, 78 mg/kg,
80 mg/kg, 82 mg/kg, 84 mg/kg, 86 mg/kg, 88 mg/kg, 90 mg/kg, 92
mg/kg, 94 mg/kg, 96 mg/kg, 98 mg/kg, 100 mg/kg, 110 mg/kg, 120
mg/kg, 130 mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 170 mg/kg, 180
mg/kg, 190 mg/kg or 200 mg/kg.
[0222] It should be understood that dose ranges comprising the
above listed doses are also included in the present invention. For
example, any of the above doses may be a lower part or an upper
part of a dose range that is included in the present invention.
Even further, it should be understood that all lists or collections
of numerical values used throughout the present application also
are intended to include ranges of the numerical values wherein any
of the listed numerical values can be the lower part or upper part
of a range. These ranges are intended to be included in the present
invention.
[0223] In some embodiments, a compound of the invention, e.g.,
Compound A' or Compound A, may be administered at a dose of from
about 10 to about 1000 mg, about 20 to about 750 mg, about 50 to
about 500 mg, about 75 to about 400 mg, about 100 to about 300 mg,
about 110 to about 290 mg, about 120 to about 280 mg, about 130 to
about 270 mg, about 140 to about 260 mg, about 150 to about 250 mg,
about 160 to about 240 mg, about 170 mg to about 230 mg, about 180
mg to about 220 mg, about 190 mg to about 210 mg, or about 200 mg.
In another embodiment, the compound of the present invention, e.g.,
Compound A' or compound A, may be administered intravenously at a
dose of about 5 to about 500 mg, about 10 to about 400 mg, about 25
to about 300 mg, about 50 to about 200 mg, about 50 to about 150
mg, about 60 to about 140 mg, about 70 mg to about 130 mg, about 80
mg to about 120 mg, about 90 mg to about 110 mg, or about 100 mg.
In one embodiment, the compound of the invention, e.g., Compound A'
or Compound A, may be administered orally at a dose of from about 5
to about 800 mg, about 10 to about 700 mg, about 25 to about 600
mg, about 50 to about 500 mg, about 100 to about 400 mg, about 150
to about 350 mg, about 200 mg to about 340 mg, about 250 mg to
about 330 mg, about 270 mg to about 320 mg, about 280 to about 310,
or about 300 mg.
[0224] In an embodiment, the compound of the invention, e.g.,
Compound A' or Compound A, may be administered intravenously at the
dose of about 100 mg, about 200 mg, or about 300 mg. In another
embodiment, the compound of the invention, e.g., Compound A' or
Compound A, may be administered orally at the dose of about 300 mg,
about 600 mg, or about 900 mg.
[0225] In one embodiment, an oral dose of compound of the
invention, e.g., Compound A' or Compound A is 3 times larger than
an intravenous dose of the compound of the invention, e.g.,
Compound A' or Compound A.
[0226] It will be understood that for all listed embodiments the
dose of the compound of the invention, e.g., Compound A' or
Compound A, is also an effective amount of the compound of the
invention, e.g., Compound A' or Compound A.
[0227] In one embodiment, the effective amount of a compound of the
present invention, e.g., Compound A or Compound A', when
administered orally, is from about 10 to about 1000 mg, about 20 to
about 750 mg, about 50 to about 500 mg, about 75 to about 400 mg,
about 100 to about 300 mg, about 110 to about 290 mg, about 120 to
about 280 mg, about 130 to about 270 mg, about 140 to about 260 mg,
about 150 to about 250 mg, about 160 to about 240 mg, about 170 mg
to about 230 mg, about 180 mg to about 220 mg, about 190 mg to
about 210 mg, or about 200 mg. In another embodiment, the effective
amount of a compound of the present invention, e.g., Compound A or
compound A', when administered intravenously, is from about 5 to
about 500 mg, about 10 to about 400 mg, about 25 to about 300 mg,
about 50 to about 200 mg, about 50 to about 150 mg, about 60 to
about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120
mg, about 90 mg to about 110 mg, or about 100 mg.
[0228] In one embodiment, a salt of a compound of the present
invention is a hydrochloride salt. In another embodiment, a salt of
a compound of the present invention is a tosylate salt. In a
further embodiment, a compound of the present invention is
administered orally as a free base or as a tosylate salt. In
another embodiment, a compound of the present invention is
administered intravenously as the hydrochloride salt. In yet
another embodiment, a compound of the present invention is a mixed
salt, e.g., mixed hydrochloride and tosylate salt.
[0229] In another embodiment, a compound of the present invention,
e.g., Compound A or Compound A', may be administered once per day,
either intravenously or orally.
[0230] In some embodiments, a compound of the present invention,
e.g., Compound A or Compound A', may be administered for at least 3
days, at least 7 days, at least 14 days, at least 21 days, at least
30 days or at least 60 days. For example, the administration of the
compound of the present invention may last for 3 days to 7 days,
for 3 days to 14 days, for 3 days to 21 days, for 3 days to 30
days, for 3 days to 60 days, for 7 days to 14 days, for 7 days to
21 days, for 7 days to 30 days, for 7 days to 60 days, for 14 days
to 21 days, for 14 days to 30 days, for 14 days to 60 days, for 21
days to 30 days, for 21 days to 60 days, or for 30 days to 60
days.
[0231] For example, a compound of the present invention, e.g.,
Compound A or Compound A', may be administered for 3 days, 4 days,
5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,
13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20
days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27
days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34
days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41
days, 42 days, 43 days, 44 days, 45 days, 46 days, 47 days, 48
days, 49 days, 50 days, 51 days, 52 days, 53 days, 54 days, 55
days, 56 days, 57 days, 58 days, 59 days or 60 days.
[0232] In some embodiments, the method comprises administering to
the subject one or more loading doses of the compound, followed by
one or more maintenance doses of the compound. In one embodiment,
the one or more loading dose may be greater than the one or more
maintenance dose.
[0233] In some embodiments, administration of a compound of the
present invention, e.g., Compound A or Compound A', to a subject
may comprise administering one or more loading doses of the
compound, followed by one or more maintenance doses of the
compound. In some embodiments, the one or more loading dose of the
compound may be greater than the one or more maintenance dose of
the compound. For example, the loading dose may be about 200 mg,
while the maintenance dose may be about 150 mg, 100 mg or 50 mg; or
the loading dose may be about 400 mg, while the maintenance dose
may be about 300 mg, 250 mg, 200 mg, 150 mg, 100 mg or 50 mg; or
the loading dose may be about 100 mg, while the maintenance dose
may be about 75 mg, about 50 mg or about 25 mg.
[0234] The loading dose of the compound of the invention and the
maintenance dose of the compound of the invention may be
administered via same routes or different routes. For example, the
loading dose may be administered intravenously and the maintenance
dose may be administered orally. In other embodiments, both the
loading dose and the maintenance dose may be administered orally,
or the loading dose and the maintenance dose may be administered
intravenously.
[0235] In some embodiments, the loading dose of the compound of the
invention, e.g., Compound A' or Compound A, may be an oral dose or
an intravenous dose administered twice daily, and the maintenance
dose may be an oral dose or an intravenous dose administered once
daily. For example, the compound of the invention, e.g., Compound
A' or Compound A, may be administered as an intravenous loading
dose of 100 mg twice daily, followed by an intravenous maintenance
dose of 100 mg once daily. In another example, the compound of the
invention, e.g., Compound A' or Compound A, may be administered as
an intravenous loading dose of 100 mg twice daily, followed by an
oral maintenance dose of 300 mg once daily. In yet another example,
the compound of the invention, e.g., Compound A' or Compound A, may
be administered as an oral loading dose of 300 mg twice daily,
followed by an oral maintenance dose of 300 mg once daily.
[0236] The term "treating" or "treatment" refers to the
amelioration or diminishment of one or more symptoms of the
disorder, e.g., a bacterial infection, to be treated.
[0237] The term "prophylaxis", "prevent", or "prevention" means to
prevent or reduce the risk of a bacterial infection.
[0238] A bacterium is "easily produced or disseminated" if the
bacterium can be produced or disseminated by routine methods,
processes, or techniques and with common materials, reagents,
equipment, etc. available in the art, or by methods, processes, or
techniques and with materials, reagents, equipment, etc. which are
accessible to and can be operated or used by a lay person having
little or no training in the art.
[0239] The term "moderate morbidity" refers to morbidity of no less
than 10%, no less than 15%, no less than 20%, no less than 25%, no
less than 30%, no less than 35%, no less than 40%, or no less than
45%. The term "high morbidity" refers to morbidity of no less than
50%, no less than 55%, no less than 60%, no less than 65%, no less
than 70%, no less than 75%, no less than 80%, no less than 85%, no
less than 90%, or no less than 95%.
[0240] The term "moderate mortality" refers to mortality of no less
than 10%, no less than 15%, no less than 20%, no less than 25%, no
less than 30%, no less than 35%, no less than 40%, or no less than
45%. The term "high mortality" refers to mortality of no less than
50%, no less than 55%, no less than 60%, no less than 65%, no less
than 70%, no less than 75%, no less than 80%, no less than 85%, no
less than 90%, or no less than 95%.
[0241] The term "resistance" or "resistant" refers to the
antibiotic/organism standards as defined by the Clinical and
Laboratories Standards Institute (CLSI) and/or the Food and Drug
Administration (FDA).
[0242] The term "subject" includes animals which are subject to a
bacterial infection. Examples of subjects include animals such as
farm animals (e.g., cows, pigs, horses, goats, rabbits, sheep,
chickens, etc.), lab animals (mice, rats, monkeys, chimpanzees,
etc.), pets (e.g., dogs, cats, ferrets, hamsters, etc.), birds
(e.g., chickens, turkeys, ducks, geese, crows, ravens, sparrows,
etc.), primates (e.g., monkeys, gorillas, chimpanzees, bonobos, and
humans), and other animals (e.g., squirrels, raccoons, mice, rats,
etc.). In one embodiment, the subject is a mouse or rat. In one
embodiment, the subject is a cow, a pig, or a chicken. In one
embodiment, the subject is a human.
[0243] The compounds of the present invention may be administered
by any route which allows the compounds to perform its intended
function, e.g., treat or prevent a bacterial infection. Examples of
routes include orally, intravenously, and topically. In one
embodiment, a compound of the present invention is administered
orally. In another embodiment, a compound of the present invention
is administered intravenously.
[0244] The term "effective amount" includes the amount of a
compound of the present invention needed to treat or prevent a
bacterial infection. For example, an effective amount describes an
efficacious level sufficient to achieve the desired therapeutic
effect through the killing of bacteria and/or inhibition of
bacterial growth. In one embodiment, the effective amount is
sufficient to eradicate the bacterium or bacteria causing the
infection. In some embodiments, the effective amount is the dose of
the compound of the invention, e.g., Compound A' or Compound A,
that is administered to the subject, e.g., orally or
intravenously.
[0245] The term "about" refers to a range of values which can be
15%, 10%, 8%, 5%, 3%, 2%, 1%, or 0.5% more or less than the
specified value. For example, "about 10%" can be from 8.5% to
11.5%. In one embodiment, the term "about" refers to a range of
values which are 5% more or less than the specified value. In
another embodiment, the term "about" refers to a range of values
which are 2% more or less than the specified value. In another
embodiment, the term "about" refers to a range of values which are
1% more or less than the specified value.
[0246] The structures of the compounds of the present invention may
include double bonds or asymmetric carbon atoms. Such compounds can
occur as racemates, racemic mixtures, single enantiomers,
individual diastereomers, diastereomeric mixtures, and cis- or
trans- or E- or Z-double bond isomeric forms. Such isomers can be
obtained in substantially pure form by classical separation
techniques and by stereochemically controlled synthesis.
Furthermore, the structures and other compounds and moieties
discussed in the present invention also include all tautomers
thereof.
[0247] The compounds of the present invention may be basic or
acidic, and are capable of forming a wide variety of salts with
various acids or bases. The acids that may be used to prepare
pharmaceutically acceptable salts of the compounds of the present
invention that are basic are those that form non-toxic acid
addition salts, such as HCl salt, HBr salt, HI salt, nitrate,
sulfate, bisulfate, phosphate, acid phosphate, isonicotinate,
acetate, lactate, salicylate, citrate, acid citrate, tartrate,
bitartrate, pantothenate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methane sulfonate, ethanesulfonate, benzene
sulfonate, p-toluenesulfonate (i.e., tosylate) and palmoate. The
bases that may be used to prepare pharmaceutically acceptable salts
of the compounds of the present invention that are acidic are those
that form a non-toxic base salts, such as those salts containing
alkali metal cations (e.g., Na.sup.+ and K.sup.+), alkaline earth
metal cations (e.g., Mg.sup.++ and Ca.sup.++), and amines.
[0248] The compounds of the present invention that are basic in
nature are capable of forming a wide variety of salts with various
inorganic and organic acids. The acids that may be used to prepare
pharmaceutically acceptable acid addition salts of the compounds of
the present invention that are basic in nature are those that form
nontoxic acid addition salts, i.e., salts containing
pharmaceutically acceptable anions, such as the hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate,
acid phosphate, isonicotinate, acetate, lactate, salicylate,
citrate, acid citrate, tartrate, pantothenate, bitartrate,
ascorbate, succinate, maleate, gentisinate, fumarate, gluconate,
glucaronate, saccharate, formate, benzoate, glutamate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate (i.e., tosylate), and palmoate (i.e.,
1,1'-methylene-bis-(2 hydroxy-3-naphthoate)) salts. Although such
salts must be pharmaceutically acceptable for administration to a
subject, e.g., an animal, it is often desirable in practice to
initially isolate the compounds of the present invention from the
reaction mixture as pharmaceutically unacceptable salts and then
simply convert the latter back to the free base compounds by
treatment with an alkaline reagent and subsequently convert the
latter free base to pharmaceutically acceptable acid addition
salts. The acid addition salts of the compounds of the present
invention are readily prepared by treating the compounds with a
substantially equivalent amount of the chosen mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon careful evaporation of the
solvent, the desired solid salts are readily obtained.
[0249] In one embodiment, a salt of a compound of the present
invention is a hydrochloride salt. In another embodiment, a salt of
a compound of the present invention is a tosylate salt. In a
further embodiment, a compound of the present invention is
administered orally as a free base or as a tosylate salt. In
another embodiment, a compound of the present invention is
administered intravenously as the hydrochloride salt. In yet
another embodiment, a compound of the present invention is a mixed
salt, e.g., mixed hydrochloride and tosylate salt.
[0250] It is to be understood that wherever values and ranges are
provided herein, e.g., in ages of subject populations, dosages, and
time durations, etc., all values and ranges encompassed by these
values and ranges, are meant to be encompassed within the scope of
the present invention. Moreover, all values in these values and
ranges may also be the upper or lower limits of a range.
[0251] The compounds of the present invention can be synthesized by
using art recognized techniques, such as those described in U.S.
Pat. Nos. 6,846,939 and 7,553,828, and US Patent Publication No.
20080287401, the contents of each of which are incorporated herein
by reference in their entirety. The compounds thus obtained can be
further purified, for example, by flash column chromatography, high
performance liquid chromatography, crystallization, or any known
purification method.
[0252] In one embodiment, the compounds of the present invention
can be synthesized according to the synthetic scheme as shown below
and as described in US 20080287401:
##STR00017##
[0253] In one embodiment, the compounds of the present invention
can be purified by chromatography, which comprises injecting an
aqueous low pH solution of the compound into an HPLC in a polar
organic solvent gradient, and combining the product fractions.
Selection of suitable acidic mobile phases enhances process
stability and selectivity. Organic and mineral acid mobile phases
are effective at separating by-products, including epimer
impurities, and closely-eluting by products through pH control or
choice of acid. Acidic mobile phases also protect against oxidative
degradation of the compound. For example, the low pH solution has a
pH of about 2-3. Examples of solutions that can used include 0.1%
aqueous solutions of methane sulfonic acid and 0.1% aqueous
solutions of trifluoroacetic acid. An isocratic gradient of 94% of
the aqueous solution and 6% acetonitrile or another polar organic
solvent may be used to purify the compound from epimeric and
closely eluting by-products. The resulting aqueous product
fractions can be combined, and the pH may be adjusted to about
4.0-4.5 using a base (e.g., NaOH). Hydrophobic impurities and
oxidative degradents of the compound may be removed by washing the
aqueous solution with a non-polar organic solvent (e.g.,
CH.sub.2Cl.sub.2). The organic layers may be discarded and the
aqueous layers may be combined and retained. It should be noted
that the organic solvents, such as methylene chloride, may be used
to selectively remove late-eluting hydrophobic impurities such as
4-carbonyl by-products and other oxidative degradents from the
acidic aqueous solution of the compound. The pH of the combined
aqueous layers was adjusted to neutral pH (e.g., about 7.5 to about
8.5). The pH may be adjusted by the addition of a base, such as
NaOH. The neutral solution may then be washed with a non-polar
organic solvent, such as methylene chloride. It should be noted
that selective pH adjustment to neutral pH ranges may also allow
the compound to be extracted into the organic solvent while
retaining undesired (3-epimer and by-products in the aqueous
phase.
[0254] The reagents that may be used in the synthetic routes
described in the above patents may include, for example, solvents,
reagents, catalysts, and protecting group and deprotecting group
reagents. The synthetic routes may also include additional steps,
either before or after the steps described specifically therein, to
add or remove suitable protecting groups in order to ultimately
allow synthesis of the desired tetracycline compounds. In addition,
various synthetic steps may be performed in an alternate sequence
or order to give the desired compounds. For example, compounds may
be further modified via conventional chemical transformations to
produce the compounds of the present invention. Synthetic chemistry
transformations and protecting group methodologies (protection and
deprotection) are known in the art and include, e.g., those
described in R. Larock, Comprehensive Organic Transformations, VCH
Publishers (1989); T.W.
Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd
Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser
and Fieser's Reagents for Organic Synthesis, John Wiley and Sons
(1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic
Synthesis, John Wiley and Sons (1995).
[0255] The synthetic routes described in the above patents are used
only for illustrative purposes. One skilled in the art, in view of
the schemes and the examples provided therein, would appreciate
that all of the compounds of the present invention can be made by
similar methods that are well known in the art.
[0256] The efficacy of the compound of the present invention in
treating or preventing a bacterial infection may be assessed by
using common methods known in the art. In one embodiment, the
efficacy may be determined by Minimum Inhibition Concentration
(MIC) assay. For example, the compound of the present invention is
serially diluted and then added to the growth medium, e.g.,
cation-adjusted Mueller Hinton broth (CAMHB) of the bacterial
culture. The lowest concentration of the compound of the present
invention that inhibits 50% or 90% bacterial growth (i.e.,
MIC.sub.50 or MIC.sub.90) is determined and, if necessary, compared
with MIC.sub.50 or MIC.sub.90 of other antibiotics. In another
embodiment, the efficacy may be determined through in vivo assays
known in the art (e.g., animal experiments). For example, the
compound of the present invention is administered to experimental
animals (e.g., mice and rats) at decreasing amounts. The lowest
amount of the compound of the present invention that treats the
experimental animal (e.g., ameliorates symptoms of a bacterial
infection, prolongs the survival time of the animal, and allows
animal to survive the bacterial infection) or prevents the
experimental animals from being infected by the bacterium or
developing any symptoms of the infection is determined and, if
necessary, compared with the lowest amount of other antibiotics
which achieves the same results.
[0257] The invention also pertains to pharmaceutical compositions
comprising a therapeutically effective amount of a compound of the
present invention (e.g., Compound A) or a salt thereof and,
optionally, a pharmaceutically acceptable carrier. In a further
embodiment, the invention pertains to a pharmaceutical composition
comprising from about 10 to about 1000 mg of a compound of the
present invention (e.g., Compound A or Compound A') or a salt
thereof and a pharmaceutically acceptable carrier. In a further
embodiment, the pharmaceutically acceptable carrier is acceptable
for oral administration. In another further embodiment, a compound
of the present invention is a free base or a tosylate salt.
[0258] In yet another further embodiment, the composition comprises
from about 20 to about 750 mg, about 50 to about 500 mg, about 75
to about 400 mg, about 100 to about 300 mg, about 110 to about 290
mg, about 120 to about 280 mg, about 130 to about 270 mg, about 140
to about 260 mg, about 20 about 150 to about 250 mg, about 160 to
about 240 mg, about 170 mg to about 230 mg, about 180 mg to about
220 mg, about 190 mg to about 210 mg, or about 200 mg of a compound
of the present invention (e.g., Compound A or Compound A') or a
salt thereof.
[0259] In another embodiment, the invention also pertains to a
pharmaceutical composition comprising from about 5 to about 500 mg
of a compound of the present invention (e.g., Compound A or
Compound A') or a salt thereof and a pharmaceutically acceptable
carrier suitable for intravenous administration. In yet another
further embodiment, the composition comprises from about 10 to
about 400 mg, about 25 to about 300 mg, about 50 to about 200 mg,
about 50 to about 150 mg, about 60 to about 140 mg, about 70 mg to
about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110
mg, or about 100 mg of a compound of the present invention (e.g.,
Compound A or Compound A') or a salt thereof.
[0260] The language "pharmaceutically acceptable carrier" includes
substances capable of being co-administered with a compound of the
present invention (e.g., Compound A or Compound A'), and which
allow the compound to perform its intended function, e.g., treat or
prevent a bacterial infection. Suitable pharmaceutically acceptable
carriers include but are not limited to water, salt solutions,
alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,
amylose, magnesium stearate, talc, silicic acid, viscous paraffin,
perfume oil, fatty acid mono glycerides and diglycerides,
petroethral fatty acid esters, hydroxymethyl cellulose,
polyvinylpyrrolidone, etc. The pharmaceutical preparations can be
sterilized and if desired mixed with auxiliary agents, e.g.,
lubricants, preservatives, stabilizers, wetting agents,
emulsifiers, salts for influencing osmotic pressure, buffers,
colorings, flavorings and/or aromatic substances and the like which
do not deleteriously react with the compounds of the present
invention.
[0261] The compounds of the present invention and pharmaceutically
acceptable salts thereof can be administered via either the oral,
parenteral or topical routes. In general, these compounds are most
desirably administered in effective dosages, depending upon the
weight and condition of the subject being treated and the
particular route of administration chosen. Variations may occur
depending upon the species of the subject being treated and its
individual response to the medicament, as well as on the type of
pharmaceutical formulation chosen and the time period and interval
at which such administration is carried out.
[0262] The compounds and pharmaceutical compositions of the present
invention may be administered alone or in combination with other
known compositions for treating tetracycline responsive states in a
subject. The language "in combination with" a known composition is
intended to include simultaneous administration of the composition
of the present invention and the known composition, administration
of the composition of the present invention first, followed by the
known composition, and administration of the known composition
first, followed by the composition of the present invention. Any of
the therapeutically composition known in the art for treating
tetracycline responsive states can be used in the methods of the
present invention.
[0263] The compounds and pharmaceutical compositions of the present
invention may be administered alone or in combination with
pharmaceutically acceptable carriers or diluents by any of the
routes previously mentioned, and the administration may be carried
out in single or multiple doses. For example, the compounds of the
present invention can be administered advantageously in a wide
variety of different dosage forms, i.e., they may be combined with
various pharmaceutically acceptable inert carriers in the form of
tablets, capsules, lozenges, troches, hard candies, powders,
sprays, creams, salves, suppositories, jellies, gels, pastes,
lotions, ointments, aqueous suspensions, injectable solutions,
elixirs, syrups, and the like. Such carriers include solid diluents
or fillers, sterile aqueous media and various non-toxic organic
solvents, etc. Moreover, oral pharmaceutical compositions can be
suitably sweetened and/or flavored. In general, the
therapeutically-effective compounds of the present invention are
present in such dosage forms at concentration levels ranging from
about 5.0% to about 70% by weight.
[0264] For oral administration, tablets containing various
excipients such as microcrystalline cellulose, sodium citrate,
calcium carbonate, dicalcium phosphate, and glycine may be employed
along with various disintegrants such as starch (and preferably
corn, potato or tapioca starch), alginic acid, and certain complex
silicates, together with granulation binders like
polyvinylpyrrolidone, sucrose, gelatin, and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate, and talc are often very useful for tabletting purposes.
Solid compositions of a similar type may also be employed as
fillers in gelatin capsules; preferred materials in this connection
also include lactose or milk sugar as well as high molecular weight
polyethylene glycols.
[0265] When aqueous suspensions and/or elixirs are desired for oral
administration, the active ingredient may be combined with various
sweetening or flavoring agents, coloring matter or dyes, and, if so
desired, emulsifying and/or suspending agents as well, together
with such diluents as water, ethanol, propylene glycol, glycerin,
and various like combinations thereof.
[0266] For parenteral administration (including intraperitoneal,
subcutaneous, intravenous, intradermal, or intramuscular
injection), solutions of the compounds of the present invention in
either sesame or peanut oil or in aqueous propylene glycol may be
employed. The aqueous solutions should be suitably buffered if
necessary and the liquid diluent first rendered isotonic. These
aqueous solutions are suitable for intravenous injection purposes.
The oily solutions are suitable for intra-articular, intramuscular
and subcutaneous injection purposes. The preparation of all these
solutions under sterile conditions is readily accomplished by
standard pharmaceutical techniques well known to those skilled in
the art. For parenteral application, examples of suitable
preparations include solutions, preferably oily or aqueous
solutions as well as suspensions, emulsions, or implants, including
suppositories. Therapeutic compounds may be formulated in sterile
form in multiple or single dose formats such as being dispersed in
a fluid carrier such as sterile physiological saline or 5% saline
dextrose solutions commonly used with injectables.
[0267] For enteral application, particularly suitable are tablets,
dragees, or capsules having talc and/or carbohydrate carrier binder
or the like, the carrier preferably being lactose and/or corn
starch and/or potato starch. A syrup, elixir or the like can be
used wherein a sweetened vehicle is employed. Sustained release
compositions can be formulated including those wherein the active
component is protected with differentially degradable coatings,
e.g., by microencapsulation, multiple coatings, etc.
EXEMPLIFICATION OF THE INVENTION
Example 1
##STR00018##
[0269] Minocycline hydrochloride was dissolved in methylsulfonic
acid or hydrofluoric acid with methyl sulfonic anhydride.
N-hydroxymethyl phthalimide was added to the reaction mixture. The
mixture was stirred at 20-35.degree. C. until the reaction was
complete. The acid solution was added to an ice/water mixture and
the triflic salt was readily precipitated, filtered and collected.
The salt was re-dissolved in acetone and brought to a neutral pH
with base. The product was precipitated by the addition of water.
The product was isolated as a mixture of the bis and tris alkylated
product. The isolated material of this reaction was enriched in the
desired bis ratio (90%).
[0270] The solid was suspended in the EtOH. Aminolysis was carried
out by using methylamine A phthalamide by-product precipitated as
the reaction progressed and was removed by filtration. The light
yellow solid product was precipitated out by the addition of about
1.5 volumes of t-butylmethylether to the reaction mixture, and
collected through a simple filtration that left many small
impurities and methylamine reagent in the solution. Further
purification of the compound was performed through re-slurrying
with methanol.
[0271] Compound 4 as freebase was transferred to a hydrogenation
vessel which was charged with methanol and aldehyde. An inactivated
Pd/C catalyst was charged and the vessel was pressurized with
hydrogen gas. The reaction mixture was hydrogenated under hydrogen
pressure around 30 Psi for about 24 hours. When conversion of
compound 4 to 1 was complete, the solution was filtered and washed
through a Celite pad. At this point the reaction mixture contained
very low .beta. C-4 epimer, around 3-7%.
[0272] The product (1) was worked up and isolated selectively from
its impurities. The pH of the solution was adjusted to about 4.5
with concentrated HCl and the solution was washed with
dichloromethane. Sulfites were added to the aqueous layer and the
product was extracted with dichloromethane at pH of about 7 to 8 to
selectively recover the preferred epimer product (e.g., a). The
dichloromethane layers were combined and concentrated, and 2 L of
n-heptane was added to precipitate the product. Further
purification was obtained by repeating the work-up procedure with
or without t-butylmethylether to dissolve the crude product.
[0273] 9-(2',2'-dimethylpropyl aminomethyl)-minocycline
dihydrochloride (200 mg, 1 eq.), DMF and trimethylacetaldehyde (45
.mu.L, 1 eq.) were combined in 40 mL flasks and stirred.
Triethylamine (150 .mu.L, 3 eq.) was then added. After stirring at
room temperature for several minutes, NaBH(OAc).sub.3 (175 mg, 2
eq.) and InCl.sub.3 (9 mg, 0.1 eq.) was added. After one hour, the
reaction was clear and red. The reaction was quenched with
methanol, the solvent was removed, and Compound A was obtained.
Example 2
[0274] Crude 9-(2',2'-dimethylpropyl aminomethyl) minocycline
freebase (40 g) was dissolved in 150 mL of buffer A (0.1% aqueous
solution of methane sulfonic acid--MSA) and the pH was adjusted to
2-3 with MSA. The solution was filtered and injected into an HPLC
and the product was eluted with an isocratic gradient of 94% buffer
A and 6% acetonitrile. The product fraction collection was
initiated when the product peak was detected. Each fraction was
analyzed and an acceptance criterion of greater than 80% AUC of the
main peak was used for the early product fractions. When combining
fractions, the level of impurities and relative concentration of
the pooled fractions was factored into the selection criteria that
meet the final product specifications. To the product fractions was
added a 10% aqueous solution of sodium sulfite equal to 10% of the
original volume of the collected fractions.
[0275] A product fraction volume of 3.5 liters (including sodium
sulfite) was collected and the pH was adjusted to 4.0-4.5 using a
solution of sodium hydroxide. The aqueous solution was washed with
2 liters of dichloromethane and the organic layer was separated and
discarded. The pH of the aqueous layer was adjusted to 7.5-8.5
using sodium hydroxide and the product was extracted four times
with 2.4 liters of dichloromethane. The pH was readjusted to
7.5-8.5 with sodium hydroxide, prior to each extraction.
[0276] The four dichloromethane layers were combined and
concentrated to about 200 ml, which was then added slowly (over a
period of about 10 minutes) to a vigorously stirred n-heptane (2.5
L). The suspension was stirred for about 10 minutes at room
temperature and diluted slowly (over a period of 5 minutes) with
n-heptane 1.5 L. The slurry was cooled to 0-5.degree. C. and
stirred for 1-2 hours. The suspended solid was filtered and washed
with 3.times.150 mL portions of n-heptane. The product was dried
under vacuum at 40.degree. C. for at least 24 hours until a
constant weight was achieved and the levels of all residual
solvents were within specification. Approximately 13.6 g of
9-(2',2'-dimethylpropyl aminomethyl) minocycline freebase was
isolated as a yellow solid. The off-cuts were isolated in a similar
manner and yielded 1.64 g.
Example 3
[0277] Bacterial inoculums were prepared by suspending into
cation-adjusted Mueller-Hinton broth (CAMHB) colonies from 18-24 h
B. anthracis, B. pseudomallei, or B. mallei plates, or 42-48 h F.
tularensis or Y. pestis plates that were incubated at 35.degree. C.
Sheep Blood agar (SBA) plates were used for B. anthracis and Y.
pestis, chocolate agar plates for F. tularensis, and Trypticase Soy
agar (TSA) plates for B. pseudomallei and B. mallei. Suspended
cultures were diluted with CAMHB to a bacterial cell density of
10.sup.5 CFU/mL adjusted based on OD.sub.600. Conversion factors
used for each pathogen were: B. anthracis (3.82.times.10.sup.7
CFU/mL/OD), B. mallei and B. pseudomallei (5.0.times.10.sup.8
CFU/mL/OD), Y. pestis (5.34.times.10.sup.8 CFU/mL/OD), and F.
tularensis (3.89.times.10.sup.10 CFU/mL/OD). 50 .mu.L of the
adjusted dilution was added to each well of 96-well plates for a
final inoculum of .about.5.times.10.sup.4 CFU/well.
[0278] The inoculated 96-well plates were incubated at 35.degree.
C. Antibiotics were serially diluted two-fold in 50 .mu.L of CAMHB
and added to individual wells of the plates. For all steps with F.
tularensis, CAMHB was supplemented with 2% Isovitalex (Becton
Dickinson). The antibiotic ranges were 8-0.0039.about..mu.g/ml or
64-0.03125 .mu.g/ml based on a final well volume of 100 .mu.L after
inoculation. MICs were determined by the microdilution method in
the 96-well plates according to CLSI guidelines. MICs were
determined visually at 18-24 h or 42-48 h (for F. tularensis and Y.
pestis) and also by reading the plates at 600 nm (SpectroMax M2,
Molecular Devices). Quality control of the antibiotic stocks was
established by using E. coli ATCC 25922, P. aeruginosa ATCC 27853,
and S. aureus ATCC 29213. Inoculums of these control bacteria were
prepared as described above from 18-24 h SBA plates. Conversion
factors were: E. coli (6.83.times.10.sup.8 CFU/mL/OD), P.
aeruginosa (5.74.times.10.sup.10 CFU/mL/OD), and S. aureus
(2.07.times.10.sup.10 CFU/mL/OD).
[0279] Stock solutions of Compound A at 5.15 mg/ml were made in
100% DMSO. Prior to use, the stock solution was diluted in CAMHB
before being added to the 96-well plates as described above.
Comparator antibiotics ciprofloxacin, ceftazidime, and azithromycin
were all purchased from USP, made into 5.15 mg/ml stocks according
to the CLSI M 100-S 18 Table 4 guidelines and stored at -70.degree.
C. until use.
Example 4
[0280] Compound A was highly active against strains of Bacillus
anthracia and B. mallei, and also had significant activity against
Yersinia pestis and Franciscella tularensis, demonstrating
excellent MIC.sub.50 and MIC.sub.00 values against these target
pathogens (Table 1). The MIC values for Compound A were comparable
to those for doxycycline which is currently recommended for
treatment of diseases caused by these pathogens. Unlike
doxycycline, however, Compound A is expected to be active against
strains possessing either efflux or ribosomal mechanisms of
resistance.
TABLE-US-00001 TABLE 1 In Vitro Activity of Compound A Historical
Data Compound A Ciprofloxacin Tetracycline Doxycycline Y. pestis
MIC range 0.125-2 0.0039-0.0625 0.25-2 0.0625-2 (.mu.g/mL)
MIC.sub.50 1 0.01563 0.5 0.5 MIC.sub.90 1 0.03125 2 1 B. anthracis
MIC range <0.03125-0.0625 0.03125-.25 <0.03125-1
0.03125-0.0625 (.mu.g/mL) MIC.sub.50 0.03125 0.0625 <0.03125
0.03125 MIC.sub.90 0.0625 0.125 0.125 0.0625 F. tularensis MIC
range 0.5-2 0.0078-0.25 <0.03125-1 0.03125 (.mu.g/mL) MIC.sub.50
1 0.0078 0.125 0.25 MIC.sub.90 2 0.01563 0.5 0.5 B. mallei MIC
range <0.03125-0.5 0.0625-1 0.01563-0.5 0.015563-0.5 (.mu.g/mL)
MIC.sub.50 0.125 0.5 0.125 0.0625 MIC.sub.90 0.25 1 0.25 0.125 B.
pseudomallei MIC range 2->64 0.5-32 1->8 0.0625 (.mu.g/mL)
MIC.sub.50 64 2 2 0.5 MIC.sub.90 >64 4 >8 8
Example 5
[0281] The in vitro activity of Compound A was assessed in
independent laboratories using bacteria isolated from clinical
specimens. For all aerobic or facultatively anaerobic organisms,
MICs were determined by the broth microdilution method recommended
by the Clinical & Laboratory Standards Institute (CLSI, M7-A7,
2006) using cation adjusted Mueller-Hinton Broth (CAMHB, DIFCO
Lot#5230237). When testing fastidious organisms such as
streptococci, the CAMHB was supplemented with 3-5% lysed horse
blood (Hemostat Lot# H06036). Haemophilus Test Medium (HTM) was
used for testing Haemophilus influenzae. A selected group of
microorganisms was also tested by agar dilution using the methods
specified by CLSI document M7-A7, 2006 using plain Mueller-Hinton
Agar (Difco Lots 1303004 & 5011641) for testing the majority of
the isolates or supplemented with 5% sheep blood (Hema Resource Lot
#1127-100140-04) for testing the streptococci. All broth media used
was less than 12 hours old at the time of MIC tray production.
[0282] All anaerobic strains were tested by broth microdilution and
agar dilution using the methods specified by the CLSI (M11-A6,
2004). Brucella broth (BBL Lot #5227153), supplemented with 5
.mu.g/ml of hemin (Sigma Lot #89K0914), 1 .mu.g/ml of vitamin K1
(Sigma Lot#120K1413) and 5% lysed horse blood (Hemostat Lot
#H06036) was used for testing all anaerobic strains. In addition,
all strains were tested using the agar dilution method using
Brucella agar (BBL Lot #6160970) supplemented with 5 .mu.g/ml of
hemin, 1 .mu.g/ml of vitamin K1 and 5% lysed sheep blood (Hema
Resource Lot #1127-100140-04). Fresh broth less than 12 hours old
was used for preparing MIC trays. The agar dilution plates were
poured on the same day as testing.
[0283] Compound A exhibited activity against almost all of the
clinical isolates tested (Table 2). This included isolates that
were resistant to current tetracyclines such as doxycycline (Table
2). Compound A was also active against pathogens expected to be
encountered in ABSSSI and CABP irrespective of resistance to
commonly used antibiotics, including tetracycline. The in vitro
activity of Compound A was not affected by serum or lung
surfactant, important characteristics consistent with potential
utility in infections involving the lower respiratory tract.
TABLE-US-00002 TABLE 2 Activity of Compound A versus Doxycycline
Against Bacterial Pathogens Compound A/Doxycycline MIC.sub.50
MIC.sub.90 Class Species #Isolates (.mu.g/mL) (.mu.g/mL) Gram-
Staphylococcus aureus (MSSA) 52 0.25/0.12 0.25/0.25 positive
Staphylococcus aureus (MRSA) 111 0.25/0.12 0.25/2 pathogens.sup.b
Coagulase-negative staphylococci 152 0.25/0.25 1/2 Enterococcus
faecalis (VSE) 107 0.25/8 0.5/8.sup. Enterococcus facecalis (VRE)
47 0.12/0.25 0.25/8 Enterococcus faecium (VSE) 56 0.12/0.12
0.12/16.sup. Enterococcus faecium (VRE) 100 0.12/8 0.12/8
Streptococcus pneumonia 104 0.12/0.25 0.12/8 Streptococcus
pneumoniae (PRSP) 51 0.12/8 0.12/8 Streptococcus pyogenes 104
0.12/25.sup. 0.12/0.25 Streptococcus agalactiae 53 0.25/8
0.25/16.sup. Gram- Haemophilus influenza 105 0.5/0.5 1/1 negative
Moraxella catarrhalis 105 0.25/0.25 0.25/0.25 pathogens.sup.b
Escherichia coli 203 2/8 4/>32 Enterobacter aerogenes 51 2/2 4/4
Enterobacter cloacae 62 2/4 16/16 Klebsiella pneumonia 204 2/2
8/>32 Proteus mirabilis 11 16/16 32/>32 Salmonella spp. 52
2/4 8/32 Shigella spp. 51 1/1 2/32 Pseudomonas aeruginosa 22 32/32
64/32 Acinetobacter baumannii 53 0.25/0.25 4/2 Burkholderia cepacia
29 2/4 64/>32 Anaerobic Bacteroides fragilis 100 1/8 4/16
pathogens.sup.b Clostridium difficile 27 0.12/0.03 0.12/1
Clostridium perfringens 100 1/2 4/8 Atypical Legionella pneumophila
25 0.25/1 0.25/1 pathogens Chlamydia pneumonia 3 0.25/ND.sup.a
0.25/ND .sup.aND--Not Tested. .sup.bMICs determined by broth
microdilution using fresh media. Data from Brown, S., and M. M.
Traczewski, 2007. MK-2764: In vitro Spectrium of Activity,
Confirmation of Disk Mass, Agar Dilution Validation and Short Term
Stability using Fresh Media. The Clinical Microbiology Institute
Report, Wilsonville, OR.
Example 6
[0284] The in vivo activity of Compound A was demonstrated in
multiple animal models of infection using various pathogens. As
shown in Table 3, Compound A was generally as potent or more potent
and as effective or more effective than, minocycline, vancomycin,
and linezolid.
TABLE-US-00003 TABLE 3 Animal Models of Infection Infecting
bacterial Type of PD.sub.50.sup.a/ED.sub.50.sup.b species Animal
Infection (mg/kg) S. pneumoniae Mice acute systemic 0.09-0.14 Mice
pulmonary 7.4 Mice pulmonary 11-27.1 (neutropenic) Mice thigh wound
0.14-0.75 (neutropenic) S. aureus Mice acute systemic 0.4 Mice
thigh wound 5.9 (neutropenic) E. faecalis Mice renal infection 4.5
H. influenza Mice pulmonary 4.7 E. coli Mice urinary tract 4.3
.sup.aPD.sub.50 (Protective Dose, 50%) defined as the dose required
to achieve 50% survival. .sup.bED.sub.50 (Effective Dose, 50%)
defined as the dose required to achieve a 2 log10 reduction in
bacterial burden (cfu/g) at the target organ compared to untreated
controls.
Example 7
[0285] The in vivo activity of Compound A (omadacycline) was tested
in lethal Y. pestis post exposure prophylactic (PEP) infection
model. BALB/c 6-8 week old female mice were infected by 29.9
LD.sub.50s of Y. pestis (CO92) via whole body aerosol. Ten mice per
each group were used. Compound A was administered intraperitoneally
twenty-five hours post-infection at the doses of 5, 10, 20 and 40
mg/kg every 12 hours for 7 days. Doxycycline at the doses of 5, 10,
20 and 40 mg/kg and ciprofloxacin at the dose of 15 mg/kg were used
as positive controls. Mice were followed for 14 days
post-infection, and percent survival was determined.
[0286] The results are presented in FIG. 1 which demonstrates that
Compound A at 40 mg/kg is more effective as doxycycline at 40 mg/kg
and is at least as effective or ciprofloxacin at 15 mg/kg at
treating Y. pestis infection for at least 14 days post-infection.
In this experiment, MIC for Compound A was 1 .mu.g/mL, for
doxycycline was 0.5 .mu.g/mL, and for ciprofloxacin is 0.06
.mu.g/mL. Also, PD.sub.50 for Compound A was 23.5 (range of 20.1 to
27.0 mg/kg), while PD.sub.50 for doxycycline was 29.7 (range of
20.7 to 38.8).
Example 8
[0287] The in vivo activity of Compound A (omadacycline) was tested
in lethal B. anthracis post exposure prophylactic (PEP) infection
model. BALB/c 6-8 week old female mice were infected by 30.5
LD.sub.50s of B. anthracis AMES strain via whole body aerosol. Ten
mice per each group were used. Compound A was administered
intraperitoneally twenty-four hours post-infection at the doses of
0.75, 2.5, 7.5, and 15 mg/kg every 12 hours for 14 days.
Doxycycline at the doses of 0.75, 2.5, 7.5 and 15 mg/kg and
ciprofloxacin at the dose of 30 mg/kg were used as positive
controls. Mice were followed for 41 days post infection, and
percent survival was determined.
[0288] The results are presented in FIG. 2 which demonstrates that
Compound A is as effective as doxycycline or ciprofloxacin at
treating B. anthracis infection for at least 41 days
post-infection. In this experiment, MIC for Compound A was <0.03
.mu.g/mL, while MIC for both doxycycline and ciprofloxacin is 0.03
.mu.g/mL. Also, PD.sub.50 for Compound A was 0.8 (range of 0.6 to
1.1 mg/kg), while PD.sub.50 for doxycycline was 2.0 (range of 1.4
to 2.6).
Example 9
[0289] The in vivo activity of Compound A (omadacycline) was tested
in lethal B. mallei post exposure prophylactic (PEP) infection
model. BALB/c 6-8 week old female mice were infected by 59.6
LD.sub.50s of B. mallei (China 7) via whole body aerosol. Ten mice
per each group were used. Compound A was administered
intraperitoneally twenty-five hours post-infection at the doses of
0.75, 2.5, 7.5 and 15 mg/kg every 12 hours for 21 days. Doxycycline
at the concentrations of 0.75, 2.5, 7.5 and 15 mg/kg and
azithromycin at the concentration of 15 mg/kg were used as positive
controls. Mice were followed for 55 days post-infection, and
percent survival was determined.
[0290] The results are presented in FIG. 3 which demonstrates that
Compound A is as effective as doxycycline or azithromycin at
treating B. mallei infection. In this experiment, MIC for Compound
A was 0.25 .mu.g/mL, for doxycycline was 0.06 .mu.g/mL, and for
azithromycin was 0.5 .mu.g/mL. Also, PD.sub.50 for Compound A was
<0.75 mg/kg, and PD.sub.50 for doxycycline was also <0.75
mg/kg. All of the dosing group animals except one survived all
treatments. No control group animals survived.
EQUIVALENTS
[0291] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments and methods described
herein. Such equivalents are intended to be encompassed by the
scope of the present invention. All patents, patent applications,
and literature references cited herein are hereby expressly
incorporated by reference.
* * * * *