Methods and compositions for increasing antibiotic activity

Patent metadata

Field	Value
Publication number	US-9820967-B2
Application number	US-201514797951-A
Country	US
Kind code	B2
Filing date	Jul 13, 2015
Priority date	Jul 18, 2014
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

One aspect of the invention provides a method of inhibiting an efflux pump in a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione, thereby inhibiting the efflux pump. Another aspect provides a method of inhibiting proliferation of a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby inhibiting the proliferation of the bacteria. Another aspect of the invention provides a method of increasing the efficacy of an antibiotic, the method comprising contacting a bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby increasing the efficacy of the antibiotic. Another aspect provides a method of inhibiting development of antibiotic resistance in a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby inhibiting development of resistance to the antibiotic. Another aspect of the invention provides a pharmaceutical composition for treating a bacterial infection comprising an effective amount of 3,4-dibromopyrrole-2,5-dione in a pharmaceutically acceptable excipient.

First claim

What is claimed is:

1. A method of inhibiting an efflux pump in a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione, thereby inhibiting the efflux pump.

2. A method of inhibiting proliferation of a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby inhibiting the proliferation of the bacteria.

3. A method of inhibiting survival of a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby inhibiting the survival of the bacteria.

4. A method of increasing the efficacy of an antibiotic, the method comprising contacting a bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby increasing the efficacy of the antibiotic.

5. A method of inhibiting development of antibiotic resistance in a bacteria, the method comprising contacting the bacteria with 3,4-dibromopyrrole-2,5-dione and an antibiotic, thereby inhibiting the development of resistance to the antibiotic.

6. The method of claim 1 , wherein the bacteria is Gram-positive or Gram-negative.

7. The method of claim 1 , wherein the bacteria is Escherichia coli, Salmonella, Enterobacter, Klebsiella, Neisseria , or Pseudomonas.

8. The method of claim 7 , wherein the bacteria is multidrug resistant Escherichia coli.

9. The method of claim 1 , wherein the efflux pump is a resistance nodulation cell division pump.

10. The method of claim 9 , wherein the resistance nodulation cell division pump is selected from the group consisting of AcrAB-TolC, MexAB-OprM, and MexXY-OprM.

11. The method of claim 2 , wherein the antibiotic is selected from the group consisting of a fluoroquinolone, aminoglycoside, macrolide, beta-lactam, tetracycline, cephalosporins, and chloramphenicol.

12. The method of claim 11 , wherein the antibiotic is ciprofloxacin, levofloxacin, kanamycin, erythromycin, oxacillin, piperacillin, amoxicillin, or azithromycin.

13. The method of claim 2 , wherein the method reduces the minimum inhibitory concentration of the antibiotic by at least 4-fold, 8-fold, or 16-fold.

14. The method of claim 1 , wherein the method inhibits efflux from the efflux pump by at least about 75%, 85%, 95% or more.

15. A pharmaceutical composition for treating a bacterial infection comprising an effective amount of 3,4-dibromopyrrole-2,5-dione and an effective amount of an antibiotic selected from fluoroquinolone, aminoglycoside, macrolide, beta-lactam, tetracycline, cephalosporins, and chloramphenicol in a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15 , wherein the antibiotic is ciprofloxacin, levofloxacin, kanamycin, erythromycin, oxacillin, piperacillin, amoxicillin, or azithromycin.

17. The pharmaceutical composition of claim 15 , wherein the bacterial infection is multidrug resistant.

18. A kit for treating a bacterial infection in a subject, the kit comprising an effective amount of 3,4-dibromopyrrole-2,5-dione and an antibiotic selected from fluoroquinolone, aminoglycoside, macrolide, beta-lactam, tetracycline, cephalosporins, and chloramphenicol.

19. The kit of claim 18 , wherein the antibiotic is ciprofloxacin, levofloxacin, kanamycin, erythromycin, oxacillin, piperacillin, amoxicillin, or azithromycin.

Assignees

• Woods Hole Oceanographic Inst

Inventors

• Mincer Tracy
• Whalen Kristen

Classifications

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/65

  Tetracyclines · CPC title

• A61K31/7048

  having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin} · CPC title

• A61K31/4015 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title