Antibacterial metallacarborane-peptide hybrids target membrane potential in a non-lytic mode and show resistance to proteolysis

The urgent need for innovative antibiotics has driven the exploration of unconventional chemical frameworks to combat multidrug-resistant (MDR) bacteria. Metallacarboranes, particularly 3,3'-cobalt bis(dicarbollide) (COSAN) and its iodinated derivative I-COSAN, have demonstrated promise as antimicrobial agents because of their abiotic origins, stability, low toxicity, and unique physicochemical properties. In this study, we developed and characterized a novel class of metallacarborane-peptide hybrids with amphiphilic properties designed to mimic natural antimicrobial peptides (AMPs). These hybrids, consisting of cationic di- and tripeptides conjugated with COSAN or I-COSAN, exhibit broad-spectrum antibacterial and antibiofilm activities. By modulating the lipophilicity and charge of the hybrids, we optimized them for high antibacterial performance and biocompatibility. Mechanistic investigations revealed that the hybrids targeted the bacterial membrane potential, causing depolarization and ATP synthesis inhibition without inducing membrane lysis. These effects were accompanied by the overproduction of reactive oxygen species (ROS) and structural deformation of bacterial cells. The enhanced stability of these hybrids against proteolysis further underscores their therapeutic potential. This proof-of-concept study introduces metallacarborane‒peptide hybrids as a promising new class of antimicrobial agents with broad-spectrum activity, high stability, and a nonlytic mode of action.