Purine Metabolism in Mycobacterium tuberculosis as a Target for Drug Development

Tuberculosis remains a serious health problem throughout the world, and new drugs are needed to help control this disease. We have identified several purine nucleoside analogs that exhibit selective activity against Mycobacterium tuberculosis. The lead compound in this series is 2-methyl-adenosine (methyl-Ado), which is active against proliferating and nonproliferating bacteria due to its ability to inhibit protein synthesis. Methyl-Ado is activated by adenosine kinase that is expressed in M. tuberculosis cells. The primary intracellular metabolite is 2-methyl-AMP, although some methyl- ATP was also produced in the cells. Adenosine kinase has been purified from M. tuberculosis cells and its biochemical activity has been characterized and compared to that of the human homolog. The gene for adenosine kinase has been determined to be Rv2202c, which had been putatively identified as a sugar kinase. Because very little is known about purine metabolism in M. tuberculosis, we have initiated studies to characterize the enzymes that are involved in salvage of purine nucleosides. We believe that enhanced knowledge of the characteristics of the enzymes involved in purine salvage in M. tuberculosis should aid in the rational design of more potent purine analogs that can selectively inhibit M. tuberculosis replication. Compounds in this class should be active against strains of M. tuberculosis that are resistant to current agents used to treat this disease and may also target latent disease.