A poly(trisulfide) prodrug with antimicrobial activity

Antimicrobial resistance is a growing threat to human health and agriculture. Sulfur-containing compounds and elemental sulfur have a long history of use as antimicrobials, but challenges related to solubility and formulation have limited their broad application. Recent advances in sulfur polymer chemistry have enabled the development of novel sulfur-rich materials with antimicrobial activity. However, most of these materials are water-insoluble, limiting their use in biomedical and agricultural applications. Here, we report the synthesis of a linear poly(trisulfide) via photochemical ring-opening polymerization of a cyclic trisulfide monomer bearing a carboxylic acid. Deprotonation of the carboxylic acid renders the poly(trisulfide) fully water soluble, with concomitant chain scission via S-S cleavage. The resulting poly(trisulfide) oligomers exhibited potent antifungal activity against Candida albicans (MIC < 8 µg/mL), and stronger inhibition of the Gram-positive bacterium Staphylococcus aureus (MIC = 16 µg/mL) compared to the Gram-negative Escherichia coli (MIC > 512 µg/mL). In control experiments, the monomer did not show potent antifungal or antibacterial activity. This work demonstrates a simple and controllable synthesis of a poly(trisulfide) species that serves as a prodrug: treatment with NaOH converts the polymer to water-soluble oligomers with antimicrobial activity. This approach is a new direction for biological applications of sulfur polymers and a new strategy to address antimicrobial resistance.

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