Antibacterial Cyclic Oligo(disulfide)s with Tunable Hydrophilicity Dictate Membrane Interactions and Distinct Metabolic Interference

Abstract

Abstract To combat drug-resistant bacteria, antimicrobial agents with tunable and multi-modal mechanisms are urgently needed. While membrane-disrupting polymers have been widely explored, precisely regulating their membrane interactions and downstream metabolic effects remains challenging. Here, using naturally occurring lipoic acid, we designed cationic cyclic oligo(disulfide)s (CCOs) that induce targeted membrane depolarization and trigger distinct downstream metabolic responses. CCOs exhibit species-specific killing mechanisms: membrane depolarization in Staphylococcus aureus and reactive oxygen species induction in Escherichia coli. The cationic-to-hydrophilic ratio governs both membrane interactions and metabolic regulation. Coarse-grained molecular dynamics simulations revealed that fully cationic CCO1 adsorbs via electrostatic forces, whereas CCO2-64%, bearing partial hydrophilic groups, relies on a balance of electrostatic and van der Waals interactions, underlying its enhanced antibacterial selectivity. Transcriptomic analysis further showed that CCO1 disrupts ribosome assembly and sulfur-containing amino acid metabolism, while CCO2-64% downregulates oxidoreductase activity and nitrogen metabolism. With favorable biosafety and potent efficacy against methicillin-resistant S. aureus in a murine cutaneous abscess model, CCOs represent a tunable antimicrobial system with considerable clinical translation potential.