Proton-motive force stimulation to potentiate aminoglycoside antibiotics against persistent bacteria

Patent metadata

Field	Value
Publication number	US-9480696-B2
Application number	US-201214115528-A
Country	US
Kind code	B2
Filing date	May 4, 2012
Priority date	May 4, 2011
Publication date	Nov 1, 2016
Grant date	Nov 1, 2016

Abstract

Provided herein are compositions and methods to improve treatment of chronic infections, and reduce, delay, or inhibit formation of biofilms, using specific combinations of aminoglycoside antibiotics and high, localized concentrations of one or more PMF stimulating compounds. These novel methods are easily adapted to clinical settings as toxicity and efficacy of the antibiotics and metabolites used have already been studied in vivo, and as dosing for both the antibiotics and metabolites are known. These approaches and therapeutic methods are also useful with non-metabolic chemicals that induce proton-motive force in bacteria.

First claim

We claim:

1. A method for treating a chronic or persisting bacterial infection, the method comprising administering to a subject having or at risk for a chronic or persisting bacterial infection an effective amount of an aminoglycoside antibiotic and an effective amount of at least one proton motive force (PMF) stimulating compound selected from fructose and pyruvate as an adjuvant.

2. A method for treating a chronic or persisting bacterial infection, comprising: administering to a subject having a chronic or persisting bacterial infection and undergoing treatment with an aminoglycoside antibiotic, an effective amount of at least one proton motive force stimulating compound selected from mannitol, fructose and pyruvate as an adjuvant.

3. The method of claim 1 , wherein the aminoglycoside antibiotic is streptomycin, gentamicin, kanamycin A, tobramycin, neomycin B, neomycin C, framycetin, paromomycin, ribostamycin, amikacin, arbekacin, bekanamycin (kanamycin B), dibekacin, spectinomycin, hygromycin B, paromomycin sulfate, netilmicin, sisomicin, isepamicin, verdamicin, astromicin, neamine, ribostamycin, or lividomycin.

4. The method of claim 1 , wherein the aminoglycoside antibiotic is gentamicin and the at least one PMF stimulating compound is fructose.

5. The method of claim 1 , wherein the aminoglycoside antibiotic is tobramycin and the at least one PMF stimulating compound is pyruvate.

6. The method of claim 1 , wherein the bacterial infection comprises one or more gram positive or gram negative organisms.

7. The method of claim 1 , wherein the bacterial infection comprises one or more of Escherichia coli or Staphylococcus aureus.

8. The method of claim 1 , wherein the bacterial infection comprises one or more of species of Pseudomonas, Proteus, Serratia, Citrobacter, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter , or Enterococcus.

9. The method of claim 1 , wherein the subject has a urinary tract infection; infective endocarditis; an infection of the skin, nose, ears, and/or eyes; external burns; an infection associated with cystic fibrosis; a prosthetic valve infection; a native valve infection; an infection associated with endometritis; an infection associated with febrile neutropenia; an intraabdominal infection; meningitis; an infection associated with osteomyelitis; an infection associated with pelvic inflammatory disease; an infection associated with peritonitis; an infection associated with pneumonia; an infection associated with pyelonephritis; an infection associated with skin or soft tissue; an infection associated with surgery, or an infection associated with tularemia.

10. A method of inhibiting or delaying biofilm formation or colonization on a surface of a counter, a bench top, a medical or laboratory equipment, a tool, a medical device, or an in-dwelling medical device, the method comprising contacting the surface with an effective amount of an aminoglycoside antibiotic and an effective amount one or more PMF stimulating compounds selected from fructose and pyruvate.

11. The method of claim 10 , wherein the surface is the surface of an in-dwelling medical device.

12. The method of claim 1 , wherein the PMF stimulating compound is mannitol or pyruvate and is administered at a concentration of at least 5 mM.

13. The method of claim 1 , wherein the aminoglycoside antibiotic and PMF stimulating compound are administered topically, intraveously, intramuscularly, or via oral administration.

14. The method of claim 13 , wherein the aminoglycoside antibiotic and PMF stimulating compound are administered intravenously.

15. The method of claim 14 , wherein the PMF stimulating compound is administered at a concentration of at least 25 mM.

16. The method of claim 15 , wherein the PMF stimulating compound is adminstered at a concentration of at least 100 mM.

17. A method for treating a chronic or persisting bacterial infection associated with an in-dwelling medical device, the method comprising administering to a subject having said infection an effective amount of an aminoglycoside antibiotic and an effective amount of at least one proton motive force (PMF) stimulating compound selected from mannitol, glucose, fructose, and pyruvate as an adjuvant.

18. The method of claim 17 , wherein the aminoglycoside antibiotic is gentimicin and the PMF stimulating compound is mannitol.

19. The method of claim 17 , wherein the aminoglycoside antibiotic is gentimicin and the PMF stimulating compound is pyruvate.

20. The method of claim 17 , wherein the PMF stimulating compound is mannitol or pyruvate and is administered at a concentration of at least 5 mM.

21. The method of claim 17 , wherein the aminoglycoside antibiotic and PMF stimulating compound are administered topically, intraveously, intramuscularly, or via oral administration.

22. The method of claim 17 , wherein the aminoglycoside antibiotic and PMF stimulating compound are administered intravenously.

23. The method of claim 17 , wherein the PMF stimulating compound is administered at a concentration of at least 25 mM.

24. The method of claim 17 , wherein the PMF stimulating compound is adminstered at a concentration of at least 100 mM.

25. The method of claim 2 , wherein the aminoglycoside antibiotic is streptomycin, gentamicin, kanamycin A, tobramycin, neomycin B, neomycin C, framycetin, paromomycin, ribostamycin, amikacin, arbekacin, bekanamycin (kanamycin B), dibekacin, spectinomycin, hygromycin B, paromomycin sulfate, netilmicin, sisomicin, isepamicin, verdamicin, astromicin, neamine, ribostamycin, or lividomycin.

26. The method of claim 2 , wherein the aminoglycoside antibiotic is gentamicin and the at least one PMF stimulating compound is fructose.

27. The method of claim 2 , wherein the aminoglycoside antibiotic is tobramycin and the at least one PMF stimulating compound is pyruvate.

28. The method of claim 2 , wherein the bacterial infection comprises one or more gram positive or gram negative organisms.

29. The method of claim 2 , wherein the bacterial infection comprises one or more of Escherichia coli or Staphylococcus aureus.

30. The method of claim 2 , wherein the bacterial infection comprises one or more of species of Pseudomonas, Proteus, Serratia, Citrobacter, Enterobacter, Klebsiella, Acinetobacter , or Enterococcus.

31. The method of claim 2 , wherein the subject has a urinary tract infection; infective endocarditis; an infection of the skin, nose, ears, and/or eyes; external burns; an infection associated with cystic fibrosis; a prosthetic valve infection; a native valve infection; an infection associated with endometritis; an infection associated with febrile neutropenia; an intraabdominal infection; meningitis; an infection associated with osteomyelitis; an infection associated with pelvic inflammatory disease; an infection associated with peritonitis; an infection associated with pneumonia; an infection associated with pyelonephritis; an infection associated with skin or soft tissue; an infection associated with surgery, or an infection associated with tularemia.

32. The method of claim 2 , wherein the infection is associated with Cystic fibrosis.

33. The method of claim 2 , wherein the infection is a urinary tract infection.

34. The method of claim 2 , whe

Assignees

• Collins James J
• Allison Kyle R
• Brynildsen Mark P
• Univ Boston

Inventors

• Collins James J
• Allison Kyle R
• Brynildsen Mark P

Classifications

• A61K31/7004

  Monosaccharides having only carbon, hydrogen and oxygen atoms · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K31/047

  having two or more hydroxy groups, e.g. sorbitol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title