A novel metal-based antibiotic containing an N-heterocyclic carbene ligand with multiple modes of actions

Metal complexes with N-heterocyclic carbene (NHC) ligands are a novel class of organometallic antibiotics with promising antibacterial activity. In this work we aimed to unravel the mode of action of a novel metal-based antibiotic containing an N-heterocyclic carbene ligand. Target fishing and chromatographic co-elution experiments revealed potential protein targets in Bacillus subtilis. The substance interferes with translation but also transcription in precursor incorporation assays. The proteomic response of Bacillus subtilis to treatment with sublethal concentrations of the compound was compared to responses to well-characterized antibiotics hitting the same target [2]. The comparison of proteome responses suggests that the mode of interference with the target protein is unprecedented. It further reveals similarities to the response to membrane-active antibiotics that are lytic and depolarize the membrane like gramicidin S and MP196 [1,3], which is congruent with a dose-dependent bacteriolytic activity and membrane depolarization caused by the metal-based antibiotic. We conclude that the compound is a novel promising lead structure for antibiotic development with multiple modes of action.

[1] Katsu, T. et al. Mechanism of membrane damage induced by the amphipathic peptides gramicidin S and melittin. Biochimica et biophysica acta 983, 135–141 (1989).

[2] Senges, C.H.R. et al. Comparison of Proteomic Responses as Global Approach to Antibiotic Mechanism of Action Elucidation. Antimicrobial agents and chemotherapy 65 (2020).

[3] Wenzel, M. et al. Small cationic antimicrobial peptides delocalize peripheral membrane proteins. Proceedings of the National Academy of Sciences of the United States of America 111, E1409-18 (2014).