Inhibition of Non-Essential Bacterial Targets: Discovery of a Novel Serine O-acetyltransferase Inhibitor

In ϒ-proteobacteria and actinomycetales, cysteine biosynthetic enzymes are indispensable during persistence, and become dispensable during growth or acute infection. The biosynthetic machinery required to convert inorganic sulfur into cysteine is absent in mammals, therefore it is a suitable drug target. We searched for inhibitors of Salmonella serine acetyltransferase (SAT), the enzyme that catalyzes the rate-limiting step of L-cysteine biosynthesis. The virtual screening of three ChemDiv focused libraries containing 91,243 compounds was performed to identify potential SAT inhibitors. Scaffold similarity and analysis of the overall physico-chemical properties allowed the selection of 73 compounds that were purchased and evaluated on the recombinant enzyme. Six compounds displaying an IC50 below 100 μM were identified via an indirect assay using Ellman’s reagent and then tested on a Gram-negative model organism, with one of them being able to interfere with bacterial growth via SAT inhibition.