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.