DRUGS DIRECTED AGAINST ISOPRENOID BIOSYNTHESIS

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The prevalence of multi-drug tuberculosis is increasing worldwide making the search for new anti-tuberculosis drugs imperative. A greater understanding of the basic biochemistry of M. tuberculosis will greatly facilitate this process. The overall objective of this proposal is to identify drug targets relating to cell wall synthesis in M. tuberculosis, characterize the enzymes involved and identify lead compounds for drug development. This project (3) focuses on the role played by the enzymes involved in isoprenoid biosynthesis. Isoprenoid biosynthesis can be considered one of the earliest steps in cell wall synthesis making it an ideal potential drug target. Isoprenoid compounds such as polyprenyl phosphate, menaquinone and possibly hopanoids play crucial and in some cases essential roles in mycobacterial metabolism. The observation that M. tuberculosis is susceptible to the topical antibiotic bacitracin, which inhibits isoprenoid biosynthesis demonstrates that the synthesis of the isoprenoid compounds is required for the survival of M. tuberculosis. Many bacterial isoprenoids are structurally distinct from those found in eukaryotes yet little is known about the biosynthesis of these compounds in M. tuberculosis. It was originally assumed that prokaryotes use the same biosynthetic pathways as eukaryotes for the synthesis of isoprenoids This assumption has recently been shown to be correct. We believe that identification and characterization of enzymes involved in unique and essential biosynthetic pathways will lead to the development of novel drugs for the treatment of tuberculosis. With that in mind, we have developed the following project in which we will attempt to: 1) identify compounds that inhibit 1-deoxyxylulose-5-phosphate synthase (DXS), an enzyme essential for bacterial isoprenoid biosynthesis that is not found in mammals, using a medium to high throughput assay. 2) Characterize the portions of the isoprenoid biosynthetic pathway that are unique to mycobacteria.