Proton-gated ‘ON/OFF’ antibacterial polymers: The role of tertiary amine structure and proportion in pH-dependent antibacterial activity

The amphiphilic balance between cationic and hydrophobic segments   is a critical determinant of the trade-off between antibacterial activity and biocompatibility of membranolytic polymers. In tertiary amine-based systems, this balance is dynamic and exquisitely sensitive to the pH of the tissue microenvironment. To elucidate the relationship between polymer composition and antibacterial efficacy across a physiological pH range, we developed a library of polymeric proton-gated membranolytic switches (PPGMSs) composed of butyl methacrylate and various tertiary amines. These switches achieve precise, pH-activated antibacterial activity, which is governed by the equilibrium between cationic (protonated amine) and hydrophobic butyl methacrylate and deprotonated amine domains. The switching pH of these switches increases with a higher proportion of tertiary amine or a decrease in higher amine hydrophobicity. From this library, P(E 60 /B) emerged as a lead compound, demonstrating potent activity against   E. coli   and   P. aeruginosa   under acidic conditions, and minimal cytotoxicity toward mammalian cells at neutral pH (7.4). Mechanistic studies confirmed bacterial membrane disruption as the mode of action. Crucially, P(E 60 /B) exhibited significant efficacy in a murine peritonitis model, reducing bacterial loads in a dose-dependent manner. This work establishes PPGMSs as a versatile platform for designing precision antimicrobials that leverage microenvironmental cues for selective therapy.