Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 11, Issue 5, Pages 790-797Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.9b00627
Keywords
Adjuvant therapies; Antimicrobial resistance; Cysteine biosynthesis; Nonessential targets; Serine acetyltransferase
Categories
Funding
- MSCA-ITN-2014-ETN project INTEGRATE [642620]
- Academy of Finland [277001]
- Academy of Finland (AKA) [277001, 277001] Funding Source: Academy of Finland (AKA)
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In Upsilon-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 the analysis of the overall physicochemical properties allowed the selection of 73 compounds that were purchased and evaluated on the recombinant enzyme. Six compounds displaying an IC50 <100 mu M 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.
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