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

C.      Obiol-Pardo; J.      Rubio-Martinez; S.      Imperial

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.

Keywords: Drug development, Fosmidomycin, Isoprenoid biosynthesis, MEP pathway, Mycobacterium tuberculosis, enzymes, homologous proteins, isomer, N-terminal