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Issue 7, 2013
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Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr)—evidence of a novel binding mode

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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 against Mycobacterium 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 IC50 of 17.8 μM. Analysis shows 8 binds to Mtb Dxr via a novel, non-bisubstrate mechanism. Further, the diethyl ester of 8 inhibits Mtb growth making this class of compounds interesting lead molecules in the search for new antitubercular agents.

Graphical abstract: Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr)—evidence of a novel binding mode

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Publication details

The article was received on 14 Mar 2013, accepted on 28 May 2013 and first published on 29 May 2013


Article type: Concise Article
DOI: 10.1039/C3MD00085K
Citation: Med. Chem. Commun., 2013,4, 1099-1104
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    Design of potential bisubstrate inhibitors against Mycobacterium tuberculosis (Mtb) 1-deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr)—evidence of a novel binding mode

    G. San Jose, E. R. Jackson, E. Uh, C. Johny, A. Haymond, L. Lundberg, C. Pinkham, K. Kehn-Hall, H. I. Boshoff, R. D. Couch and C. S. Dowd, Med. Chem. Commun., 2013, 4, 1099
    DOI: 10.1039/C3MD00085K

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