Sulfonium-stabilized anoplin cyclic peptides with enhanced electro-positivity for effective antimicrobial activity,...

The overuse of antibiotics has highlighted the antimicrobial peptides (AMPs) as critical agents against pathogenic bacteria. However, natural AMPs like anoplin face significant limitations, including instability and suboptimal antimicrobial efficacy. Although previous studies have demonstrated the crucial role of stable secondary structures in enhancing antimicrobial activity, concerns have arisen regarding the increased hemolytic toxicity associated with hydrophobic side chains introduced by the RCM stapling strategy. To address this challenge, we propose a sulfonium-stabilized cyclization strategy that stabilizes peptide conformation through covalent cyclization and enhances cationic charge density via sulfur-based positive charges. Notably, the improved cationic charge could help to increase the peptide's antimicrobial activity while avoiding the enhancement of hemolytic toxicity. Experimental validation revealed that sulfonium-stabilized anoplin cyclic peptides (AP[5,9]-Ph) exhibited potent antibacterial activity, extended proteolytic stability, and preserved biocompatibility. Murine wound infection models demonstrated accelerated healing rates and reduced bacterial loads in treated groups. These findings suggest that sulfonium-stabilized anoplin cyclic peptides are promising candidates for novel antimicrobial agents. Moreover, the sulfonium-stabilized stapling strategy holds potential as a powerful approach for optimizing the bioactivity of natural antimicrobial peptides like anoplin, advancing the development of new antimicrobial agents.