Each year, 8 million people develop active Tuberculosis (TB) disease and of these approximately 20% of the cases will be multiple drug resistant and 2% will be extensively drug resistant. In all, the annual death toll from TB is 2-3 million people worldwide. However, in spite of recent intensive research no new classes of anti-TB drugs have been developed for clinical use since the 1960's. In this context, designing and developing a new drug is very important. To date two different biosynthetic pathways have been reported leading to isopentenyl diphosphate, the universal precursor of isoprenoids. The mevalonate pathway is found in animals whereas the non-mevalonate or methylerythritol phosphate (MEP) pathway is found in many bacteria, some protozoa and plants. Since the MEP pathway is not found in mammalian cells, it is considered an attractive target for the development of antimicrobials, antimalarials and herbicidal agents a hypothesis that is being explored by an increasing number of researchers recently. Recently we reported enantioselective synthesis of MEP, CDPME, CDPME2P and MECPP, the substrates for assay development. In addition the kinetic studies of mycobacterial DXS, IspC, IspD, IspE, and IspF were also reported while developing assay. With the newly synthesized CDPME substrate, we developed an assay and a new IspE inhibitor was discovered showing good IC50 and MIC.References: 1. P. Narayanasamy*,H. Eoh, P. J. Brennan, and D. C. Crick. (2010) Synthesis of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate and kinetic studies of Mycobacterium Tuberculosis IspF. Chemistry and Biology, 17, 117-122.P. Narayanasamy, H. Eoh, A. C. Brown, T. Parish, P. J. Brennan, and D. C. Crick.  (2009). Expression and characterization of soluble 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase from bacterial pathogens. Chemistry and Biology, 16, 1230-1239.P. Narayanasamy,* H. Eoh, and D. C. Crick. (2008). Chemoenzymatic synthesis of 4-Diphosphocytidyl-2-C-methyl-D-erythritol: A substrate for IspE. Tetrahedron Letters, 4461-4463.

Synthesis of substrate, development of assay, and discovery of inhibitor against mycobacteria

245th National Meeting (2013)

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