Chemical Proteomics Reveals Antibiotic Targets of Oxadiazolones in MRSA

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.