Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA
Alexander T. Bakker, Ioli Kotsogianni, Liza Mirenda, Verena M. Straub, Mariana Ávalos, Richard J. B. H. N. van den Berg, Bogdan I. Florea, Gilles P. van Wezel, Antonius P. A. Janssen, Nathaniel I. Martin, Mario van der Stelt
Abstract
Phenotypic screening is a powerful approach to identify novel antibiotics, but elucidation of the targets responsible for the antimicrobial activity is often challenging in the case of compounds with a polypharmacological mode of action. Here, we show that activity-based protein profiling maps the target interaction landscape of a series of 1,3,4-oxadiazole-3-ones identified in a phenotypic screen to have high antibacterial potency against multidrug-resistant Staphylococcus aureus. In situ competitive and comparative chemical proteomics with a tailor-made activity-based probe, in combination with transposon and resistance studies, revealed several cysteine and serine hydrolases as relevant targets. Our data showcase oxadiazolones as a novel antibacterial chemotype with a polypharmacological mode of action, in which FabH, FphC, and AdhE play a central role.