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7159189 
Journal Article 
Discovery, Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor 
Bayaraa, T; Kurz, JL; Patel, KM; Hussein, WM; Bilyj, JK; West, NP; Schenk, G; Mcgeary, RP; Guddat, LW; , 
2020 
Yes 
Chemistry: A European Journal
ISSN: 0947-6539
EISSN: 1521-3765 
WILEY-V C H VERLAG GMBH 
WEINHEIM 
8958-8968 
32198779 
WOS:000544384200001 
Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections includingMycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purifiedM. tuberculosis(Mt) KARI and identified two compounds that haveK(i)values below 200 nm. InMtcell susceptibility assays one of these compounds exhibited an IC(50)value of 0.8 mu m. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex withStaphylococcus aureusKARI, which has 56 % identity withMtKARI, NADPH and Mg(2+)yielded a structure to 1.72 angstrom resolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly,Mtcell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.