The Methylerythritol Phosphate (MEP) Pathway for Isoprenoid Biosynthesis as a Target for the Development of New Drugs Against Tuberculosis

Abstract

Tuberculosis remains a major infectious disease to humans. It accounts for approximately 8-9 million new cases worldwide and an estimated 1.6 million deaths annually. Effective treatments for tuberculosis consist of a combination of several drugs administered over long periods of time. Since Mycobacterium tuberculosis often acquires multiple drug resistant mechanisms, development of new drugs with innovative actions is urgently required. The 2C-methyl-D-erythritol 4-phosphate (MEP) pathway, in charge of the essential biosynthesis of isoprenoids, represents a promising and selective target for developing new drugs against tuberculosis. To date, only fosmidomycin, a molecule that targets the second enzyme of the MEP pathway, has reached clinical trials but recent advances elucidating the structure and kinetics of the MEP enzymes are likely to change this scenario. This review describes the structure, mechanism of action and inhibitors of the seven enzymes of the MEP pathway, with special attention to the reported studies in M. tuberculosis.

Isoprenoid biosynthesis in bacterial pathogens

“…This, together with the fact that IPP synthesis in humans proceeds via the mevalonate pathway (so there are no human MEP enzyme homologues), has resulted in the MEP pathway of pathogens being considered as a drug target (reviewed by Ershov, 2007;Obiol-Pardo et al, 2011;Rohdich et al, 2005;Testa & Brown, 2003).…”

Catalytically Important Residues in E. coli 1-Deoxy-D-Xylulose 5-Phosphate Synthase

“…Since DXP is also the substrate for the synthesis of vitamins B1 (thiamin) and B6 (pyridoxol) [8] [9], MEP is the first specific intermediate of the pathway and it is accepted to name it as MEP pathway. Many pathogenic microorganisms, such as M. tuberculosis [10] and the malaria parasite P. falciparum [11], synthesize IPP and DMAPP through the MEP pathway. Given the essential role of isoprenoids in these organisms, and the fact that the MEP pathway is absent in mammals, where these precursors are exclusively synthesized via the mevalonate pathway, all the enzymes participating in the MEP pathway are potential targets for the design of inhibitors that could be used as antibiotic or antimalarial drugs [10] [11].…”

“…Many pathogenic microorganisms, such as M. tuberculosis [10] and the malaria parasite P. falciparum [11], synthesize IPP and DMAPP through the MEP pathway. Given the essential role of isoprenoids in these organisms, and the fact that the MEP pathway is absent in mammals, where these precursors are exclusively synthesized via the mevalonate pathway, all the enzymes participating in the MEP pathway are potential targets for the design of inhibitors that could be used as antibiotic or antimalarial drugs [10] [11]. In this context, DXS is one of the most attractive targets, because of its regulatory role in the biosynthesis of isoprenoids in various systems [12] [13], indicating that this enzyme catalyzes a rate-limiting step in the MEP pathway.…”

Biometallorganische Chemie mit IspG und IspH: Struktur, Funktion und Hemmung der an der Isoprenoid‐Biosynthese beteiligten [Fe4S4]‐Proteine

“…[10,[81][82][83] In den letzten drei Jahren ergaben sich deutliche Fortschritte bei der Entwicklung von IspH-und IspG-Inhibitoren, die teilweise von den Studien zum katalytischen Mechanismus profitierten -die ersten wirksamen IspH-und IspG-Inhibitoren, Alkindiphosphonate, wurden auf der Basis der vorgeschlagenen biometallorganischen Katalysemechanismen von IspH entworfen. Bis jetzt wurden drei Strategien zur Entwicklung von IspHund IspG-Inhibitoren eingesetzt: 1) Herstellung von Substratanaloga; 2) Mechanismus-basiertes, rationales Design und 3) Screening von Substanzbibliotheken.…”