Biological and Medicinal Chemistry

Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA



Phenotypic screening is a powerful approach to identify novel antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) infection, but elucidation of the targets responsible for 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 S. 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 novel antibacterial chemotype with a polypharmacological mode-of-action, in which FabH, FphC and AdhE play a central role.


Thumbnail image of manuscript A T Bakker et al 2022 chemRxiv.pdf

Supplementary material

Thumbnail image of SI A T Bakker et al 2022 chemRxiv.pdf
Supporting Information
Contains supplementary tables and figures, as well as the materials, methods and synthetic procedures and compound characterization.
Thumbnail image of Supp Data A T Bakker et al 2022 chemRxiv.xlsx
Supplementary Excel Data
Contains SAR data, extended MIC tables, and chemoproteomic/global proteomic data.