Engineering polysulfoniums for enhanced antibacterial activity with extremely minimal hemolysis

Antimicrobial peptides (AMPs) have attracted considerable research interest due to their broad-spectrum antimicrobial properties. However, the clinical translation of natural AMPs remains challenging. In this study, we present a rational design strategy for developing potent and selective antimicrobial agents by synthesizing a series of sulfonium-based polypeptoids via controlled ring-opening polymerization. By systematically modulating the hydrophobic/hydrophilic balance, chain length and cationic charge density, we obtained polysulfoniums with potent antibacterial activity while maintaining excellent hemolytic activity. Notably, the optimized polysulfonium demonstrates excellent broad-spectrum antibacterial activity against both common pathogens and multidrug-resistant bacteria, along with enhanced stability and rapid bactericidal efficacy. Further studies demonstrated that the antibacterial mechanism of polysulfoniums involves bacterial membrane disruption, which contributes to their efficacy in inhibiting biofilm formation and eradicating mature biofilms. The sulfonium-based polypeptoids represent a promising strategy for designing highly selective antibacterial polymers to combat drug-resistant bacteria.