posted on 2022-12-30, 19:35authored byAlexander
T. Bakker, Ioli Kotsogianni, Liza Mirenda, Verena M. Straub, Mariana Avalos, Richard J. B. H.
N. van den Berg, Bogdan I. Florea, Gilles P. van Wezel, Antonius P. A. Janssen, Nathaniel I. Martin, Mario van der Stelt
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.