IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters

Abstract

The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.

Phage Display on the Anti‐infective Target 1‐Deoxy‐d‐xylulose‐5‐phosphate Synthase Leads to an Acceptor–Substrate Competitive Peptidic Inhibitor

“…Spectrophotometric assay for determination of IC 50 values against E. coli IspC : Biochemical evaluation of the inhibitory activity of P7 against E. coli IspC was performed according to a protocol reported in the literature . Spectrophotometric inhibition assays with E. coli IspC were performed in 384‐well plates with a flat transparent bottom.…”

“…Spectrophotometric assay for determination of IC 50 values against E. coli IspC: Biochemical evaluation of the inhibitory activity of P7 against E. coli IspC was performed according to ap rotocol reported in the literature. [52] Spectrophotometric inhibition assays with E. coli IspC were performed in 384-well plates with aflat transparent bottom. Assay mixtures (total volume:6 0mL) contained Tris hydrochloride (100 mm,p H7.6), 4mm MnCl 2 ,5 m m DTT, 0.5 mm NADPH, 5% DMSO, 30 nm of recombinant IspC protein, and tested compound.…”

Terpenes as Potential Antimalarial Drugs

“…The use of fosmidomycin as a single-drug treatment for P. falciparum malaria has been hampered by low bioavailability, recrudescent, and rapid clearance from the parasite, although the compound has been used more successfully in combination with clindamycin [37]. Many efforts, with great results, have been made to improve the efficacy of fosmidomycin as modifications to the phosphonate group, extensions to the hydroxamic acid group [38,39], and substitution of the α-position [40,41] or, more recently, β-position [42]. The inhibition of downstream enzyme IspD (2-C-methyl-d-erythritol 4-phosphate cytidylyltransferase) which catalyzes the cytidylation of MEP to cytidine diphosphate methylerythritol (CDP-ME) is also metabolically apparent in fosmidomycin-treated cells.…”

Mechanism and inhibition of 1-deoxy-d-xylulose-5-phosphate reductoisomerase

“…With the exception of sulfur-containing isosteres [93], the potency of fosmidomycin and its acetyl analogue FR-9800098 (Fig. 9A) has never been dramatically outcompeted despite significant efforts in inhibitor design.…”