Targeting the Methyl Erythritol Phosphate (MEP) Pathway for Novel Antimalarial, Antibacterial and Herbicidal Drug Discovery: Inhibition of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase (DXR) Enzyme

Abstract

The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

“…The generated pharmacophore model was validated by a test database of 50 known inhibitors (Altincicek et al 2000;Singh et al 2007;Deng et al 2011;Jansson et al 2013) of PfDXR enzyme.…”

“…From previous literature, a test database of fifty known inhibitors (Altincicek et al 2000;Singh et al 2007;Deng et al 2011;Jansson et al 2013), having 37 active and 13 inactive compounds, was used for the validation of the pharmacophore model. The three dimensional structures of the test database compound were modelled using MOE.…”

Discovery of new targets for antimalarial chemotherapy

“…However, the antibiotic was only partially efficient since a recrudescence was observed in 50 % of cases, certainly due to the short half-life of fosmidomycin (Lell et al, 2003). Research of fosmidomycin derivatives with higher efficiency, longer half-life and better absorption are in progress as well as the study of the other enzymes of the pathway (Singh et al, 2007). Interestingly, fosmidomycin has synergic effect with the antibiotic clindamycin and randomized controlled trials in Gabon showed that the association of both molecules is as efficient as the sulfadoxine-pyrimethamine combination in malaria treatment (Oyakhirome et al, 2007).…”

The Druggable Antimalarial Target PfDXR: Overproduction Strategies and Kinetic Characterization

“…This pathway is different to that of the mevalonate pathway in the human host, making this enzyme an attractive anti-malarial drug target [1]. Recently PfDXR was genetically validated using a single cross-over strategy, and the enzyme was found to be essential for intraerythrocytic development of the parasite, further validating this enzyme as a chemotherapeutic target [2].…”