Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 145, Issue 2, Pages 1136-1143Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c10819
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Phenotypic screening identifies a series of 1,3,4-oxadiazole-3-ones as novel antibacterial compounds with a polypharmacological mode of action against multidrug-resistant Staphylococcus aureus. Activity-based protein profiling reveals several cysteine and serine hydrolases as relevant targets. This study highlights oxadiazolones as a promising antibacterial chemotype with central roles of FabH, FphC, and AdhE.
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.
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