Antimicrobial polymers at bacterial membrane interfaces

The rapid rise of antimicrobial resistance (AMR) poses a major global health challenge, undermining the effectiveness of existing antibiotics. This escalating threat underscores the urgent need for novel antimicrobial agents that are less prone to resistance development. Synthetic antimicrobial polymers (APs), inspired by host-defense peptides, have emerged as promising alternatives to conventional antibiotics. Their non-specific, membrane-disrupting mechanism makes them inherently less susceptible to bacterial resistance. This thesis aims to elucidate the mechanisms governing the selective interactions between APs and bacterial membranes. Specifically, it investigates: (i) why APs with a bottlebrush architecture generally outperform their linear counterparts; (ii) how sugar functionalization of linear cationic APs influences antibacterial selectivity and lectin recognition; and (iii) whether amphiphilicity is a necessary determinant of antimicrobial activity. A multidisciplinary approach combining microbiological, physicochemical, biochemical, spectroscopic, and microscopic techniques was employed to understand the interaction mechanisms of synthesized acrylamide-based APs with bacterial cells and model membranes. (i) Bottlebrush APs exhibited enhanced stability through intramolecular hydrogen bonding and formed unimolecular micelles presenting multivalent cationic surfaces. These features contributed to stronger membrane binding and disruption, highlighting the crucial influence of macromolecular architecture on antimicrobial performance. (ii) Linear cationic APs were modified with sugars via xanthate-supported photo-iniferter RAFT polymerization and postpolymerization reductive amination. Incorporation of sugar moieties improved cytocompatibility while maintaining antimicrobial activity. However, membrane binding was predominantly governed by electrostatic interactions rather than sugar-lectin recognition. (iii) Systematic variation of polymer amphiphilicity revealed that hydrophobicity, often associated with toxicity, is not essential for antimicrobial activity. Non-amphiphilic APs containing cationic and hydrogen-bonding functionalities displayed potent activity and reduced cytotoxicity. Their mechanism appears driven by supramolecular multivalency and surface aggregation through intermolecular hydrogen bonding. Overall, this work advances the understanding of APs–bacteria interactions and demonstrates how polymer architecture, functionalization, and amphiphilicity can be strategically tuned to design next-generation antimicrobial polymers with improved efficacy and safety.