Antibiotic activity and target discovery of three-membered natural product-derived heterocycles in pathogenic bacteria

Abstract

Oxirane, thiirane and aziridine scaffolds represent core motifs in many natural products that usually exhibit their bioactivity by a covalent modification of essential active site residues via a nucleophilic ring opening reaction. Synthesis of these three-membered heterocyclic activity based probes (ABP) was accomplished by robust standard procedures and complemented by a similar set of Michael acceptor systems. Subsequent reactivity studies against the full complement of enzymes in several bacteria revealed an individual fine-tuned affinity and reactivity of each probe that depended on the decoration as well as the heteroatom, respectively. Out of many interesting probe-target pairs, we identified thiirane-based compounds that were capable of labeling essential enzymes in S. aureus and L. monocytogenes. Corresponding to the labeling pattern we observed an antibiotic effect of these compounds against the clinically relevant pathogens L. monocytogenes as well as multiresistant S. aureus (MRSA).