Design of potential bisubstrate inhibitors against Mycobacterium 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 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.

Kinetic Characterization and Allosteric Inhibition of the Yersinia pestis 1-Deoxy-D-Xylulose 5-Phosphate Reductoisomerase (MEP Synthase)

“…Each compound was designed from resolved crystal structures of M. tuberculosis MEP synthase in complex with fosmidomycin [33] [34] and contains an amide-linked or O-linked functional group.…”

One-step synthesis of highly efficient three-dimensional Cd1-xZn x S photocatalysts for visible light photocatalytic water splitting

“…This can be ascribed to the Cd → Zn substitution in the obtained nanophotocatalysts. In addition, from Figure 4, the Raman intensities of 1-LO and 2-LO are both relatively strong and narrow, which implies its good crystallinity and ordered structure [28]. …”

Structure–Activity Relationships of the MEPicides: N-Acyl and O-Linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis

“…(8) An interesting conclusion from this work pertained to the importance of the retrohydroxamate in Dxr inhibition. The retrohydroxamate, found in fosmidomycin, FR900098, and most Dxr inhibitors reported to date, is expected to coordinate a divalent cation resident between the DXP and NADPH binding sites.…”

“…(32–34) Recently, we explored a bisubstrate approach where compounds were designed to occupy both the DXP and NADPH binding sites. (8) These compounds stem from two structure classes: an N -acyl series includes extensions of fosmidomycin’s formyl group, and an O -linked series explores substitution of the hydroxyl group of the retrohydroxamate (Figure 2). Early modeling efforts suggested that compounds from both series would act as Dxr ligands.…”

“…Early modeling efforts suggested that compounds from both series would act as Dxr ligands. (8) We refer to these compounds collectively as MEPicides (inhibitors of the MEP pathway displaying antimicrobial activity). While a small set of compounds from these series has been reported, (8, 9, 34) we describe here an expanded set of compounds from both chemical classes, SAR of these compounds against Dxr from Mtb and Yp, and antibacterial activities of these compounds against Mtb, Yp, and E. coli .…”