Synthesis of Cationic Cyclic Oligo(disulfide)s via Cyclo-Depolymerization: A Redox-Responsive and Potent Antibacterial Reagent

Antimicrobial peptides (AMPs) and synthetic topologically defined peptide mimics have been developed as alternatives to traditional small-molecule antibiotics. AMP mimetics arising from linear polymers used widely in preclinical studies have shown promise but have limited stability. Oligomers possessing cyclic topology have been proposed to have increased stability but remain understudied due to synthetic challenges and concerns over cytotoxicity. Herein, we present an efficient approach to prepare cationic, cyclic oligo(disulfide)s (CCOs) from lipoic acid derivatives. The CCOs are obtained in a one-pot cascade reaction of ring-opening polymerization preceding an in situ cyclo-depolymerization. CCOs are effective against a broad spectrum of bacteria, exhibiting a 5.43-log reduction in 5 min against Escherichia coli. They did not induce antimicrobial resistance during 24 successive passages in vitro. The cytotoxicity of CCOs is reduced by exploiting glutathione-triggered degradation. Further, fine-tuning of the cationic-to-hydrophilic ratio in CCOs has yielded improved stability in serum and a high selective index (HC50/MIC > 1280) against methicillin-resistant Staphylococcus aureus. In an infected wound rodent model, CCOs have shown substantial antibacterial potency against S. aureus, underscoring their therapeutic potential as a new class of antimicrobial agents.