Isocyanides inhibit bacterial pathogens by covalent targeting of essential metabolic enzymes.

ABSTRACT: Isonitrile natural products, also known as isocyanides, demonstrate potent antimicrobial activities, yet our understanding of their molecular targets remains limited. Here, we focus on the so far neglected group of monoisonitriles to gain further insights into their antimicrobial mode of action (MoA). Screening a focused monoisonitrile library revealed a potent S. aureus growth inhibitor with a different MoA compared to previously described isonitrile antibiotics. Chemical proteomics via competitive cysteine reactivity profiling, uncovered covalent modifications of two essential metabolic enzymes involved in the fatty acid biosynthetic process (FabF) and the hexosamine pathway (GlmS) at their active site cysteines. In-depth studies with the recombinant enzymes demonstrated co

SUBMITTER: Geißler A 

PROVIDER: S-EPMC11290450 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature