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

Abstract

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.

Arginine-Rich Peptidomimetic Ampicillin/Gentamicin Conjugate To Tackle Nosocomial Biofilms: A Promising Strategy To Repurpose First-Line Antibiotics

“…11 Although the mechanism remains unrevealed, since the capability of perturbing the bacterial membrane/wall was preserved for both conjugated antibiotics, it is likely that arginine pendants of the PAA-AG chains engage the peptidoglycan of bacteria provoking a deep penetration of the ampicillin and gentamicin side groups inside cells, thus leading to strong interactions with the cytoplasmic membrane. 12,13 It should be noticed that the functionalization of the primary amine group of ampicillin has a crucial role in helping the penetration of the drug inside bacterial membranes where b-lactams can act. However, our findings show that ampicillin preserved its antimicrobial activity toward S. aureus and E. coli strains after the conjugation with the main polymer backbone (Tables S1 and 2).…”

“…11,12 Conjugation of antibiotics with polymers is a promising strategy to improve their performance and combine different modes of action avoiding resistance phenomena. 13 In addition, very recently, arginine-rich peptides have given a cue to develop synthetic peptidomimetics with cyanophycin-like structure, named poly(argilylaspartamide-co-aspartic) acid (PAA), endowed with high stability under physiological conditions and able to deliver known antibiotics leading to potent broad-spectrum macromolecular antibiotics. 14 PAA allows conjugating FDA-approved antibiotics bearing primary amine functions such as colistin or vancomycin, preserving the farmacophore moiety and stability after the conjugation but also enhancing their activity against several pathogens.…”

“…Conjugation of antibiotics with polymers is a promising strategy to improve their performance and combine different modes of action avoiding resistance phenomena . In addition, very recently, arginine-rich peptides have given a cue to develop synthetic peptidomimetics with cyanophycin-like structure, named poly­(argilylaspartamide-co-aspartic) acid (PAA), endowed with high stability under physiological conditions and able to deliver known antibiotics leading to potent broad-spectrum macromolecular antibiotics .…”

Polytrimethylenimines: Highly Potent Antibacterial Agents with Activity and Toxicity Modulated by the Polymer Molecular Weight

“…Polymers have been investigated as antimicrobial agents in various strategies as stand-alone active molecules or conjugates with known active ingredients. − The antimicrobial potency and cytotoxicity of polycations depend on many structural parameters, e.g., type of repeating unit (r.u. ), type of positively charged group, hydrophilic–lipophilic balance, molecular architecture, and average molecular weight (MW) .…”

Ciprofloxacin peptide-based nanoparticles confer antimicrobial efficacy against multidrug-resistant bacteria

“…31 Thus, according to the idea of synergy, antibacterial materials with excellent antibacterial activity could be obtained by the copolymerization of ciprofloxacin fragments and arginine fragments. 32,33 Inspired by AMPs composed of amphiphilic groups, various antimicrobial polymers have been synthesized. 34,35 In particular, nanotechnology as a promising means has developed extremely rapidly, which have made great contributions to biomedical science.…”