Design and Evaluation of Metallacarborane-Peptide Conjugates as Novel Antimicrobial Agents

Abstract

Antimicrobial resistance (AMR) poses a significant global health threat, ranking among the top ten threats to humanity according to the World Health Organization [1]. The rise of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan-drug-resistant (PDR) pathogens is linked to their increasing insensitivity to traditional antibiotics [2]. Antimicrobial peptides (AMPs) offer a promising solution to combat drug-resistant infections [3]. These peptides, which possess cationic and hydrophobic regions, can disrupt bacterial cell membranes, leading to bacterial death [4]. However, challenges such as instability, high costs, and toxicity to normal cells must be addressed. Metallacarboranes are stable compounds consisting of one or more boron hydride clusters coordinating a metal cation. They possess unique structures and properties that make them a promising platform for the development of new antimicrobial agents [5].

In our studies, we synthesized a series of metallacarborane–ultrashort cationic peptide conjugates and comprehensively characterized their physicochemical properties. Their antimicrobial activity was evaluated by determination of minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) against representative Gram‑positive and Gram‑negative bacteria, demonstrating broad‑spectrum and predominantly bactericidal effects at low micromolar levels. In parallel, cytotoxicity and hemolysis assays were performed, enabling calculation of selectivity indices that relate MIC/MBC values to toxicity thresholds and thus substantiate the favorable therapeutic window of these conjugates.

ACKNOWLEDGMENTS

The study was supported by a grant from the National Science Centre, Poland (grant number 2023/51/D/NZ7/02609).

REFERENCES

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