title: Design of Potential Bisubstrate Inhibitors againstMycobacterium tuberculosis(Mtb) 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (Dxr)-Evidence of a Novel Binding Mode.
abstract: In most bacteria, the nonmevalonate pathway is used to synthesize isoprene units. Dxr, the second step in the pathway, catalyzes the NADPH-dependent reductive isomerization of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol-4-phosphate (MEP). Dxr is inhibited by natural products fosmidomycin and FR900098, which bind in the DXP binding site. These compounds, while potent inhibitors of Dxr, lack whole cell activity againstMycobacterium tuberculosis(Mtb) due to their polarity. Our goal was to use the Mtb Dxr-fosmidomycin co-crystal structure to design bisubstrate ligands to bind to both the DXP and NADPH sites. Such compounds would be expected to demonstrate improved whole cell activity due to increased lipophilicity. Two series of compounds were designed and synthesized. Compounds from both series inhibited Mtb Dxr. The most potent compound (8) has an IC50of 17.8 µM. Analysis shows8binds to Mtb Dxr via a novel, non-bisubstrate mechanism. Further, the diethyl ester of8inhibits Mtb growth making this class of compounds interesting lead molecules in the search for new antitubercular agents.
authors.affiliation: Department of Chemistry, George Washington University, Washington DC 20052, USA. ; Tel: 01 202 994 8405.
authors.forename: Géraldine
authors.initials: G
authors.lastname: San Jose
authors.forename: Emily R
authors.initials: ER
authors.lastname: Jackson
authors.forename: Eugene
authors.initials: E
authors.lastname: Uh
authors.forename: Chinchu
authors.initials: C
authors.lastname: Johny
authors.forename: Amanda
authors.initials: A
authors.lastname: Haymond
authors.forename: Lindsay
authors.initials: L
authors.lastname: Lundberg
authors.forename: Chelsea
authors.initials: C
authors.lastname: Pinkham
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn-Hall
authors.forename: Helena I
authors.initials: HI
authors.lastname: Boshoff
authors.forename: Robin D
authors.initials: RD
authors.lastname: Couch
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Dowd
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