Siderophore-polymer conjugates for increasing bacterial sensitivity to antibiotics
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.
1. A micelle comprising:
a conjugate comprising a water-soluble polymer covalently attached to at least one siderophore-metal ion complex wherein the 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
an antibiotic solubilized within the micelle.
2. The micelle 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).
3. The micelle of claim 2 wherein the poloxamer comprises a poly(propylene oxide) block having a weight average molecular weight of about 2,500 to about 4,500 Da.
4. The micelle of claim 1 wherein the poloxamer comprises about 10 wt % to about 80 wt % poly(ethylene oxide).
5. The micelle of claim 4 wherein the poloxamer comprises about 60 wt % to about 80 wt % poly(ethylene oxide).
6. The micelle of claim 1 wherein the water-soluble polymer is PEG having a weight average molecular weight of about 200 to about 20,000 Da.
7. The micelle of claim 6 wherein the PEG has a weight average molecular weight of about 1,000 to about 12,500 Da.
8. The micelle of claim 1 wherein the siderophore is covalently attached to the water-soluble polymer through an amide bond.
9. The micelle of claim 1 wherein the metal ion is Ga(III).
10. The micelle of claim 1 wherein the amount of antibiotic in the micelle is about 0.05 wt % to about 10 wt %.
11. The micelle of claim 1 wherein the antibiotic has a molecular weight greater than about 600 Da.
12. The micelle 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 micelle of claim 1 wherein the antibiotic has a molecular weight less than about 600 Da.
14. The micelle 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 micelle 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 micelle of claim 1 wherein the antibiotic is one or more selected from the group consisting of vancomycin, erythromycin, novobiocin, and rifampicin.
17. The micelle of claim 1 , wherein the poloxamer is covalently attached to the siderophore, the metal ion is Ga(III); 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); and the micelle comprises about 0.05 wt % to about 10 wt % of an antibiotic solubilized within the micelle selected from the group consisting of vancomycin, rifampicin, erythromycin, and novobiocin.
18. A pharmaceutical composition comprising the micelle of claim 1 and one or more pharmaceutically acceptable excipients.
19. The composition of claim 18 wherein the micelle comprises about 0.05 wt % to about 10 wt % of the antibiotic solubilized within the micelle.