Copolymerization Attenuates Membrane Perturbationin Cationic Antibacterial Polymers

Copolymerization is widely used to combine functional moieties in antimicrobial polymers, assuming their activities are retained after covalent integration. Here, we show that covalent integration can instead attenuate antibacterial membrane-perturbation activity in cationic polymethacrylates. Using quaternary ammonium- and sulfonium-containing polymers as model systems, we compared homopolymers, physical mixtures, and random and block copolymers. Rifampicin potentiation against Escherichia coli was used as a functional readout. Although the quaternary ammonium homopolymer enhanced rifampicin activity by 1024-fold, this effect was largely lost after copolymerization, with both random and block copolymers exhibiting only 2–4-fold potentiation despite identical compositions. In contrast, physical mixtures retained the activity of the highly potent component. Mechanistically, copolymer architectures preserved membrane binding but restricted postadsorption interfacial organization, thereby reducing interfacial dissipation and membrane depolarization. These findings demonstrate that identical composition does not guarantee preservation of functional output after copolymerization, highlighting the importance of intrachain organization in antimicrobial polymer design.