Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA.
Alexander T BakkerIoli KotsogianniLiza MirendaVerena M StraubMariana AvalosRichard J B H N van den BergBogdan I FloreaGilles P van WezelAntonius P A JanssenNathaniel I MartinMario van der SteltPublished in: Journal of the American Chemical Society (2022)
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.
Keyphrases
- staphylococcus aureus
- multidrug resistant
- single cell
- mass spectrometry
- methicillin resistant staphylococcus aureus
- silver nanoparticles
- living cells
- high throughput
- electronic health record
- drug resistant
- label free
- gram negative
- quantum dots
- small molecule
- klebsiella pneumoniae
- machine learning
- amino acid
- protein kinase
- candida albicans