2. Academic Validation
  3. Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA

Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA

  • J Am Chem Soc. 2023 Jan 18;145(2):1136-1143. doi: 10.1021/jacs.2c10819.
Alexander T Bakker 1,  Ioli Kotsogianni 2,  Liza Mirenda 1,  Verena M Straub 1,  Mariana Avalos 3,  Richard J B H N van den Berg 1,  Bogdan I Florea 1,  Gilles P van Wezel 3,  Antonius P A Janssen 1,  Nathaniel I Martin 2,  Mario van der Stelt 1
Affiliations

Affiliations

  • 1 Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.
  • 2 Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Leiden 2333 BE, The Netherlands.
  • 3 Department of Molecular Biotechnology, Institute of Biology Leiden, Leiden University, Leiden 2333 BE, The Netherlands.
PMID: 36584241 DOI: 10.1021/jacs.2c10819
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.

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