title: Structure-guided discovery of phenyl-diketo acids as potent inhibitors of M. tuberculosis malate synthase.
abstract: The glyoxylate shunt plays an important role in fatty acid metabolism and has been shown to be critical to survival of several pathogens involved in chronic infections. For Mycobacterium tuberculosis (Mtb), a strain with a defective glyoxylate shunt was previously shown to be unable to establish infection in a mouse model. We report the development of phenyl-diketo acid (PDKA) inhibitors of malate synthase (GlcB), one of two glyoxylate shunt enzymes, using structure-based methods. PDKA inhibitors were active against Mtb grown on acetate, and overexpression of GlcB ameliorated this inhibition. Crystal structures of complexes of GlcB with PDKA inhibitors guided optimization of potency. A selected PDKA compound demonstrated efficacy in a mouse model of tuberculosis. The discovery of these PDKA derivatives provides chemical validation of GlcB as an attractive target for tuberculosis therapeutics.
authors.affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Krieger
authors.forename: Joel S
authors.initials: JS
authors.lastname: Freundlich
authors.forename: Vijay B
authors.initials: VB
authors.lastname: Gawandi
authors.forename: Justin P
authors.initials: JP
authors.lastname: Roberts
authors.forename: Vidyadhar B
authors.initials: VB
authors.lastname: Gawandi
authors.forename: Qingan
authors.initials: Q
authors.lastname: Sun
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Owen
authors.forename: Maria T
authors.initials: MT
authors.lastname: Fraile
authors.forename: Sofia I
authors.initials: SI
authors.lastname: Huss
authors.forename: Jose-Luis
authors.initials: JL
authors.lastname: Lavandera
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ioerger
authors.forename: James C
authors.initials: JC
authors.lastname: Sacchettini
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008292:Malate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D008292:Malate Synthase