Methods and compositions for bacteria infections

Patent metadata

Field	Value
Publication number	US-9675592-B2
Application number	US-201414776965-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Jun 13, 2017
Grant date	Jun 13, 2017

Abstract

Compositions and methods are provided for treating or inhibiting a bacterial infection involving at least one antibiotic and a compound that potentiates the antibiotic activity of the antibiotic. In certain embodiments the antibiotic is a beta lactam. In further embodiments, the antibiotic is oxacillin. In additional embodiments, the potentiating compound is an inhibitor of vraSR operon expression. In specific embodiments, the bacterial infection involves an antibiotic-resistant bacteria.

First claim

The invention claimed is:

1. A method for inhibiting a staphylococcus infection comprising administering to a subject having a staphylococcus infection or at risk of a staphylococcus infection:
(a) an antibiotic, and;
(b) an antibiotic potentiator, wherein the antibiotic potentiator is a compound of the formula:

wherein R 1 may be -(4-chlorophenoxy)methyl, 1-(thiophen-2-yl)cyclopentyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 1-isopropyl-1H-pyrazol-5-yl, 2-(thiophen-2-yl)quinolin-4-yl, 2,3-dihyrdobenzo[b][1,4]dioxin-6-yl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl, 2,6-difluorophenyl, 2-bromothiophen-5-yl, 2-chlorothiophen-5-yl, 2-naphthyl, 2-phenoxyphenyl, 2-phenylquinolin-4-yl, 2-tolyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, 3,4,5-trimethoxyphenyl, 3,5-dichlorophenyl, 3,5-dimethoxyphenyl, 3-bromophenyl, 3-chlorobenzo[b]thiophen-2-yl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-n-butoxyphenyl, 3-phenoxyphenyl, 3-tolyl, 3-trifluoromethylphenyl, 4-(2,6-dimethylmorpholinosulfonyl)phenyl, 4-(2-ethylpiperidin-1-ylsulfonyl)phenyl, 4-(2-methylpiperidin-1-ylsulfonyl)phenyl, 4-(2-phenylquinoline), 4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl, 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl, 4-(3,5-dimethylpiperidin-1-ylsulfonyl)phenyl, 4-(4,4-dimethyloxazolidin-3-ylsulfonyl)phenyl, 4-(morpholinosulfonyl)phenyl, 4-(N,N-diallylsulfamoyl)phenyl, 4-(N,N-diethyl sulfamoyl)phenyl, 4-(N,N-diisobutylsulfamoyl)phenyl, 4-(N,N-dimethylsulfamoyl)phenyl, 4-(N-ethyl-N-benzyl sulfamoyl)phenyl, 4-(N-ethyl-N-n-butyl-sulfamoyl)phenyl, 4-(N-ethyl-N-phenyl sulfamoyl)phenyl, 4-(N-isopropyl-N-benzylsulfamoyl)phenyl 4-(N-methyl-N-benzylsulfamoyl)phenyl, 4-(N-methyl-N-cyclohexylsulfamoyl)phenyl, 4-(N-methyl-N-n-butyl sulfamoyl)phenyl, 4-(N-methyl-N-phenylsulfamoyl)phenyl, 4-(piperidin-1-ylsulfonyl)phenyl, 4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-benzoylphenyl, 4-benzylphenyl, 4-biphenyl, 4-chlorophenyl, 4-diphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-phenoxyphenyl, 4-tert-butylphenyl, 7-methoxybenzofuran-2-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-6-yl, benzofuran-2-yl, diphenylmethyl, methyl-4-benzoate, phenyl, or thiophen-2-yl, and
R 2 may be 1,2,3,4-tetrahydronaphthalen-6-yl, 2-(methylthio)phenyl, 2,3-dihydro-1,4-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-6-yl, 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl 2,5-dimethylphenyl, 2-bromothiophen-2-yl, 2-chlorophenyl, 2-chlorothiophen-2-yl, 2-chlorothiophen-5-yl, 2-furanyl, 2-methoxyphenyl, 2-pyridinyl, 3-(methylthio)phenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-methoxyphenyl, 3-pyridinyl, 4-chlorophenyl, 4-(methylthio)phenyl, 4-bromophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl, 4-pyridinyl, 4-trifluoromethoxyphenyl, 7-ethoxybenzofuran-2-yl, 7-methoxybenzofuran-2-yl, benzofuran-2-yl, benzyl, phenyl, or thiophen-2-yl, or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the formula:

wherein R may be 2-phenoxyphenyl, 2-bromothiophen-5-yl, or 2,5-dichlorophenyl; or
an antibiotic potentiator having the formula:

wherein R may be fluoro, or chloro, or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the formula:

wherein R 1 may be N-(4-(phenylamino)-N′-(phenyl)acetamide)amine, N-3-(N′,N′-dimethylamine)propylamine, N-(4-N′-phenylacetamide)amine, or hydroxyl, and R 2 may be tert-butyl, isopropyl, or phenyl, and R 3 may be hydrogen or chloro, or
an antibiotic potentiator having the structure:

or
an antibiotic potentiator having the formula:

wherein R may be 1H-indazol-6-yl, or 3-(4-methoxyphenoxy)methyloxadiazol-5-yl-methyl, or
an antibiotic potentiator having the formula:

wherein, R 1 and R 2 may each be separately hydrogen, methyl, chloro or methylthio, or a prodrug or comparable salt thereof.

2. The method of claim 1 , wherein the antibiotic is a penicillinase-resistant beta-lactam antibiotic.

3. The method of claim 2 , wherein the penicillinase-resistant beta-lactam antibiotic is oxacillin, methicillin, nafcillin, cloxacillin, dicloxacillin or flucloxacillin.

4. The method of claim 1 , wherein the subject has been tested for a staphylococcus infection, is diagnosed with a staphylococcus infection, is at risk of acquiring a staphylococcus infection, or has one or more symptoms of a staphylococcal infection.

5. The method of claim 1 , wherein the staphylococcus infection is Staphylococcus aureus or methicillin resistant Staphylococcus aureus (MRSA).

6. The method of claim 1 , wherein the subject has or is at risk for native valve endocarditis or prosthetic valve endocarditis.

7. The method of claim 6 , wherein the subject is administered 2-3 g of oxacillin intravenously every 4 to 6 hours.

8. The method of claim 1 , wherein the subject has or is at risk for joint infection, meningitis, osteomyelitis, pneumonia, septicemia, sinusitis, or skin or soft tissue infection.

9. The method of claim 5 , wherein the subject is administered 1-2 g of oxacillin intravenously or intramuscularly every 4 to 6 hours or 500 mg to 1 g of oxacillin orally every 4 to 6 hours.

10. The method of claim 1 , wherein treating a staphylococcal infection comprises reducing abscess formation or incidence or reducing bacterial load in the subject.

11. The method of claim 1 , further comprising administering a second antibiotic or a staphylococcal vaccine; wherein the second antibiotic is gentamicin or rifampin.

12. The method of

Assignees

• Univ Chicago
• The Board Of Regents Of The Univ Of Illinois

Inventors

• Daum Robert S
• Boyle-Vavra Susan
• Johnson Michael E

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title