Antimicrobial Amphiphilic Random Copolymers From Bio-Based Methacrylates: Effect of Chemical Composition on Activity and Selectivity

Abstract

Antibiotic resistance is a growing global threat, prompting the development of novel synthetic antimicrobial agents. Many systems are inspired by antimicrobial peptides (AMPs), which structurally are cationic amphiphilic copolymers. To mimic this type of structure, using at the same time bio-based building blocks, in this study, we synthesized 15 amphiphilic random copolymers using amino acid-derived methacrylates with different side chains (Ala, Phe, Lys) as the cationic component, and bio-based tetrahydrogeranyl methacrylate (THGA) as the hydrophobic component via Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization, yielding copolymers with varied cationic/hydrophobic balances. The antimicrobial activity of these copolymers was evaluated against E. coli and S. aureus, whereas cytotoxicity using mouse fibroblasts (L929). The results indicate that Lys-based copolymers with higher cationic content, are the most active and selective. Activity against S. aureus was influenced by the hydrophobic-hydrophilic balance, showing a non-linear trend. The cytotoxicity of these polymers also increased with the rise in cationic content. Live/dead staining, SEM, and calcein leakage assays confirmed the membrane-disrupting effects of random copolymers containing Lys as the cationic component. Furthermore, leakage was observed in liposomes mimicking bacterial membranes at concentrations below the minimum inhibitory concentration (MIC). These findings highlight the potential of bio-based amphiphilic copolymers as selective antimicrobial agents, paving the way for a more sustainable design of such pharmaceutical products.