Conjugates of Ciprofloxacin and Amphiphilic Block Copoly(2-alkyl2-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 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.

Automated summary

Conjugation of antibiotics with amphiphilic polymers enhances their antibacterial activity by optimizing the hydrophobic/hydrophilic balance of the polymer tail, resulting in increased efficacy against pathogenic bacterial strains such as Staphylococcus aureus. The mechanism of action involves the amphiphilic polymer-conjugated antibiotics concentrating within bacterial cytoplasm, compensating for the loss of affinity to the target topoisomerase IV and leading to high antibacterial activity, while also slowing down resistance development in bacteria. Furthermore, these polymer-antibiotic conjugates show activity against antibiotic-resistant strains without being cytotoxic to human cells or causing lysis of blood cells.