Siderophore-polymer conjugates for increasing bacterial sensitivity to antibiotics

Patent metadata

Field	Value
Publication number	US-10328038-B2
Application number	US-201715685954-A
Country	US
Kind code	B2
Filing date	Aug 24, 2017
Priority date	Aug 24, 2016
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

The present technology provides siderophore-polymer conjugates that enhance the sensitivity of bacteria to antibiotics, e.g., Pseudomonas, P. aeruginosa, Acinetobacter , and A. baumannii. Methods of preparing and using such conjugates to treat bacterial infections are disclosed.

First claim

What is claimed is:

1. A method of treating a human having a bacterial infection comprising administering to the subject an effective amount of:
a micelle comprising an antibiotic solubilized within the micelle, a conjugate, and optionally one or more pharmaceutically acceptable excipients;
wherein the amount of antibiotic in the micelle is about 0.05 wt % to about 10 wt %;
wherein the conjugate comprises a water-soluble polymer covalently attached to at least one siderophore-metal ion complex wherein water-soluble polymer is selected from polyethylene glycol (PEG) or a poloxamer, the siderophore is desferrioxamine B, and the metal is selected from Fe, Ga, Zn, Co, or Al; and
wherein the bacterial infection is selected from the group consisting of a Pseudomonas , Acinetobacter , P. aeruginosa , and A. baumanni infection.

2. The method of claim 1 wherein the effective amount of the composition is about 1 mg/kg to about 1000 mg/kg of the subject's body weight.

3. The method of claim 1 , wherein the water soluble polymer is a poloxamer comprising a poly(propylene oxide) block having a weight average molecular weight of about 800 to 5,000 Daltons (Da).

4. The method of claim 3 , wherein the poloxamer comprises a poly(propylene oxide) block having a weight average molecular weight of about 2,500 to about 4,500 Da.

5. The method of claim 3 , wherein the poloxamer comprises about 10 wt % to about 80 wt % poly(ethylene oxide).

6. The method of claim 3 , wherein the poloxamer comprises about 60 wt % to about 80 wt % poly(ethylene oxide).

7. The method of claim 1 , wherein the water-soluble polymer is PEG having a weight average molecular weight of about 200 to about 20,000 Da.

8. The method of claim 7 , wherein the PEG has a weight average molecular weight of about 1,000 to about 12,500 Da.

9. The method of claim 7 , wherein the siderophore is covalently attached to the water-soluble polymer through an amide bond.

10. The method of claim 1 , wherein the metal ion is Ga(III).

11. The method of claim 1 , wherein the antibiotic has a molecular weight greater than about 600 Da.

12. The method of claim 1 , wherein the antibiotic is one or more selected from the group consisting of macrolides, ketolides, streptogramin, ansamycin, aminocoumarin, and glycopeptide.

13. The method of claim 1 , wherein the antibiotic has a molecular weight less than about 600 Da.

14. The method of claim 1 , wherein the antibiotic is one or more selected from the group consisting of aminoglycosides, carbapenems, cephalosporins, monobactams, penicillins, fluoroquinolones, and rifampicin.

15. The method of claim 1 , wherein the antibiotic is one or more selected from the group consisting of erythromycin, novobiocin, gentamycin, tobramycin, doripenem, imipenem, meropenem, cefoperazone, ceftazidime, cefepime, ceftobiprole, aztreonam, carbenicillin, piperacillin/tazobactam, colistin, ciprofloxacin, levofloxacin, rifampicin, and vancomycin.

16. The method of claim 1 , wherein the antibiotic is one or more selected from the group consisting of vancomycin, rifampicin, erythromycin, and novobiocin.

17. The method of claim 1 , wherein the conjugate comprises:
a poloxamer covalently attached to a desferrioxamine B—Ga(III) complex; and
about 0.1 wt % to about 2.5 wt % of one or more antibiotics selected from the group consisting of vancomycin, rifampicin, erythromycin, and novobiocin;
wherein
the poloxamer comprises a poly(propylene oxide) block having a weight average molecular weight of 800 to 5,000 Da and about 10 wt % to about 80 wt % poly(ethylene oxide).

Assignees

• Wisconsin Alumni Res Found

Inventors

• Xiong May
• PURRO Max

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/164 Primary

  of a carboxylic acid with an aminoalcohol, e.g. ceramides · CPC title

• C12N1/20

  Bacteria; Culture media therefor · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C08G65/06

  Cyclic ethers having no atoms other than carbon and hydrogen outside the ring · CPC title