Conjugates of Ciprofloxacin and Amphiphilic Block Copoly(2-alkyl-2-oxazolines)s Overcome Efflux Pumps and Are Active against CIP-Resistant Bacteria

Conjugation of antibiotics with polymers is an emerging strategy to improve the performance of these important drugs. Here, the antibiotic ciprofloxacin (CIP) was conjugated with amphiphilic poly­(2-oxazoline) (POx) block copolymers to investigate whether the activity of the antibiotic was enhanced...

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Bibliographic Details
Published in:Molecular pharmaceutics 2021-09, Vol.18 (9), p.3532-3543
Main Authors: Romanovska, Alina, Keil, Johanna, Tophoven, Jonas, Oruc, Murat Furkan, Schmidt, Martin, Breisch, Marina, Sengstock, Christina, Weidlich, Daniela, Klostermeier, Dagmar, Tiller, Joerg C
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Cells, Cultured
Ciprofloxacin - chemistry
Ciprofloxacin - pharmacology
Drug Compounding - methods
Drug Resistance, Bacterial
Escherichia coli - drug effects
Excipients - chemistry
Humans
Mesenchymal Stem Cells
Microbial Sensitivity Tests
Oxazoles - chemistry
Staphylococcus aureus - drug effects
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Summary:Conjugation of antibiotics with polymers is an emerging strategy to improve the performance of these important drugs. Here, the antibiotic ciprofloxacin (CIP) was conjugated with amphiphilic poly­(2-oxazoline) (POx) block copolymers to investigate whether the activity of the antibiotic was enhanced due to additionally induced membrane activity. The resulting polymer–antibiotic conjugates (PACs) are an order of magnitude more active against the bacterial strain Staphylococcus aureus than CIP and show high activities against numerous pathogenic bacterial strains. Their high activity depends on an optimal hydrophobic/hydrophilic balance (HHB) of the POx tail. Mechanistic studies revealed that the derivatization of CIP required for the polymer conjugation lowers the affinity of the antibiotic to its target topoisomerase IV. However, the amphiphilic PACs are most likely concentrated within the bacterial cytoplasm, which overcompensates the loss of affinity and results in high antibacterial activity. In addition, the development of resistance in S. aureus and Escherichia coli is slowed down. More importantly, the amphiphilic PACs are active against CIP-resistant S. aureus and E. coli. The PACs with the highest activity are not cytotoxic toward human stem cells and do not lyse blood cells in saturated solution.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.1c00430