Title : Backbone-engineered sulfonium polymers: A click chemistry approach to dual antimicrobial and anticancer agents
Abstract:
Cationic materials have long been recognized as potent antimicrobial agents, with quaternary ammonium salts dominating this space for over a century. Their antibacterial mechanism primarily relies on electrostatic attraction to negatively charged bacterial membranes, followed by hydrophobic insertion of alkyl chains, leading to membrane disruption, loss of permeability control, cytoplasmic leakage, and eventual cell death. However, the extensive and prolonged use of these nitrogen-based cationic systems has contributed to the emergence of resistant bacterial strains, necessitating the development of alternative cationic motifs with improved efficacy and reduced resistance potential. In this context, trivalent sulfonium salts represent a promising yet underexplored class of cationic functionality. Herein, we report the design, synthesis, and biological evaluation of novel dual-cationic polymers incorporating both quaternary ammonium and sulfonium moieties within the polymer backbone. These materials are based on poly(β-hydroxyl amine)s synthesized via a green and efficient amine–epoxy “click” polymerization strategy carried out in aqueous media under ambient conditions. Post-polymerization functionalization through selective protonation and alkylation at nitrogen and sulfur centers enables the generation of structurally tunable cationic polymers with controlled charge density and hydrophobicity. The antimicrobial evaluation of these polymers revealed potent activity against both Gram-negative and Gram-positive bacteria, including Escherichia coli, Bacillus subtilis, and methicillin-resistant Staphylococcus aureus (MRSA). Notably, polymers bearing alkyl substituents at the nitrogen and sulphur center demonstrated exceptional antibacterial efficacy, achieving >95% growth inhibition at concentrations as low as 1–40 µg/mL. Selected candidates also showed strong activity against Bacillus subtilis and MRSA, highlighting their potential as effective agents against clinically relevant pathogens, particularly those associated with rapidly spreading skin infections. Hemocompatibility studies indicated that the majority of these polymers exhibited minimal hemolytic activity, suggesting low toxicity toward red blood cells. Mechanistic investigations supported a membrane-disruption mode of action, wherein the cationic polymers interact with and destabilize bacterial membranes, ultimately leading to cell lysis. Importantly, these materials demonstrated high selectivity for bacterial cells over mammalian cells, with selectivity indices among the highest reported for polycationic antimicrobial systems. Additionally, the most potent compounds exhibited significant biofilm disruption capability, further underscoring its therapeutic potential. Beyond their antimicrobial performance, these polymers also displayed notable anticancer activity. A series of poly(β-hydroxyl amine)s was evaluated across multiple cancer cell lines, including resistant breast and colon cancer, where they exhibited strong cytotoxicity with IC₅₀ values in the range of 8–15 µg/mL. Importantly, these compounds showed approximately 10-fold selectivity toward normal cell lines, indicating a favourable therapeutic window. Overall, this work establishes dual-functional sulfonium–ammonium polymer systems as a promising platform for next-generation therapeutics. By integrating antimicrobial and anticancer activities within a single molecular framework, these materials offer a versatile approach to address both antimicrobial resistance and cancer, paving the way for the development of multifunctional biomedical agents.
