Sulfonium-Based Antimicrobial Block Copolymers: Influence of Hydrophobicity on Biological Activity and Antibiotic Synergy.

Antimicrobial polymers (AMP) are promising therapeutics to target bacterial pathogens. Sulfonium-based AMPs offer a good balance between high antimicrobial activity and low cytotoxicity. Currently, sulfonium groups are mostly incorporated into random copolymers that combine these cations with hydrophobic and neutral hydrophilic groups. In contrast, sulfonium-based block copolymers (BCP), that structurally separate these functionalities, are less explored with structure-property relations missing. Addressing this gap, we investigated BCPs that combine the active sulfonium-based block with a neutral hydrophilic poly(polyethylene glycol methacrylate) (PPEGMA) block to improve cytocompatibility. The sulfonium cations contain varying ratios of two different hydrophobic side groups, i.e., benzyl (bz) and methyl (me) groups. By changing the bz:me ratio, we adjusted the overall polymer hydrophobicity. BCPs with bz contents above 30 mol% showed the highest activity against E. coli and S. aureus whereas those with bz contents ≤ 30 mol% exhibited the best cell viability. Thus, a bz content of 30 mol% offers optimal balance between antimicrobial activity and cytotoxicity. Combining these polymers with small molecule antibiotics penicillin G and ciprofloxacin resulted in synergistic effects, reducing the required concentrations of both polymer and antibiotic. These findings position sulfonium-based BCPs as a promising platform to boost the efficacy of conventional antibiotics.