Effect of Poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) Side-Chain Length on the Antimicrobial Activity of Tobramycin-POEGMA Conjugates against Pseudomonas aeruginosa

Abstract Polymer conjugation of cationic antibiotics has emerged as a promising strategy to improve their pharmacological properties and enhance their performance in biofilm-associated infections. Herein, we investigate the effect of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) side-chain length on the physicochemical properties, antimicrobial activity, and biocompatibility of tobramycin (Tob)-POEGMA conjugates. Three alkyne-functional POEGMA copolymers with different oligo(ethylene glycol) side-chain lengths were synthesized by reversible addition–fragmentation chain-transfer (RAFT) polymerization, and subsequently conjugated to azide-functional Tob via Cu(I)-catalyzed azide–alkyne cycloaddition. The aqueous solution behavior of the resulting conjugates was strongly dependent on side-chain length: the polymer bearing the longest side chains remained dissolved, whereas conjugates with shorter side chains self-assembled into positively charged nanoparticles. Antimicrobial evaluation against Pseudomonas aeruginosa PAO1 revealed that decreasing the POEGMA side-chain length enhanced antimicrobial activity, with the shortest-side-chain formulation exhibiting the lowest MIC90 value among the polymer conjugates. However, increased antimicrobial activity was accompanied by increased cytotoxicity toward A549 and Calu-3 epithelial cells. In contrast, longer POEGMA side-chains effectively shielded the cationic Tob residues, resulting in improved biocompatibility but reduced antimicrobial efficacy. These findings demonstrate that POEGMA side-chain length governs the balance between antimicrobial activity and cytocompatibility in Tob-POEGMA conjugates. The results further suggest that long-chain POEGMA represents a promising platform for biofilm-targeted antibiotic delivery when combined with infection-responsive linkers capable of releasing the active antibiotic at the site of infection.