Lipoic Acid Based Redox-Responsive Degradable Antimicrobial Polymers

The rise of multidrug-resistant (MDR) pathogens poses a critical threat to global health, exacerbated by the overuse of antibiotics and the lack of effective alternatives. Antimicrobial peptides (AMPs) have emerged as promising candidates due to their broad-spectrum activity and unique mechanisms of action. However, several challenges such as enzymatic degradation, high production costs, and potential cytotoxicity have hindered their clinical translation. To overcome these limitations, antimicrobial polymers (APs) inspired by AMPs have been developed using controlled/living polymerization techniques. In this study, a series of degradable, disulfide-containing antimicrobial polymers incorporating benzyl lipoate, a lipoic acid (LA) derivative, is synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization. Benzyl lipoate is prepared by modification of LA with benzyl alcohol to introduce a hydrophobic moiety and copolymerized with a primary amine-containing cationic monomer and hydrophilic co-monomers, including hydroxyethyl acrylamide (HEAm) and poly(ethylene glycol) methyl ether acrylate (PEGMEA). The resulting polymers demonstrated antimicrobial activity against drug-resistant Pseudomonas aeruginosa, improved hemocompatibility, and redox-responsive degradability. This study highlights the potential of disulfide-based APs as a next-generation strategy for combating MDR infections while ensuring controlled degradability.