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Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.

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.

SUBMITTER: Bakker AT

PROVIDER: S-EPMC9853856 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.

Bakker Alexander T AT Kotsogianni Ioli I Mirenda Liza L Straub Verena M VM Avalos Mariana M van den Berg Richard J B H N RJBHN Florea Bogdan I BI van Wezel Gilles P GP Janssen Antonius P A APA Martin Nathaniel I NI van der Stelt Mario M

Journal of the American Chemical Society 20221230 2

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 <i>Staphylococcus aureus</i>. In sit ...[more]

PMID: 36584241

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Dataset Information

Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.

Publications

Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.

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