Antibacterial Metallacarborane-Peptide Hybrids Target the Membrane Potential in a Nonlytic Mode and Are Resistant to Proteolysis

The rise of antibiotic resistance necessitates the development of innovative antimicrobial strategies. Antimicrobial peptides (AMPs), with their broad-spectrum activity and membrane-targeting mechanisms, offer an attractive alternative to conventional antibiotics but are limited by toxicity, proteolytic instability, and production costs. In this study, we report a series of novel AMP mimics combining cationic di- and tripeptides with cobalt bis(dicarbollide) (COSAN) and its iodinated analogue (I-COSAN). These metallacarborane-peptide hybrids retained the amphiphilic structure of AMPs and demonstrated potent, broad-spectrum antibacterial activity while exhibiting low hemolytic activity and cytotoxicity. Mechanistically, the best-performing conjugate induced bacterial membrane depolarization without cell lysis, accompanied by ATP depletion, reactive oxygen species overproduction, and morphological changes. Importantly, the conjugates resisted proteolytic degradation, demonstrating that a modification with a metallacarborane combines biological activity with enhanced stability. These findings introduce metallacarborane-peptide hybrids as a versatile platform for developing next-generation antimicrobials that combine the multifunctionality of AMPs with improved stability.