Abstract
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.
Keywords: Mycobacterium tuberculosis, adenosine kinase, purine metabolism, methyladenosine
Current Pharmaceutical Design
Title: Purine Metabolism in Mycobacterium tuberculosis as a Target for Drug Development
Volume: 13 Issue: 6
Author(s): William B. Parker and Mary C. Long
Affiliation:
Keywords: Mycobacterium tuberculosis, adenosine kinase, purine metabolism, methyladenosine
Abstract: 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.
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Cite this article as:
Parker B. William and Long C. Mary, Purine Metabolism in Mycobacterium tuberculosis as a Target for Drug Development, Current Pharmaceutical Design 2007; 13 (6) . https://dx.doi.org/10.2174/138161207780162863
DOI https://dx.doi.org/10.2174/138161207780162863 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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