Through the NIAID-sponsored Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF), we have identified numerous anti-Mycobacterium tuberculosis (M. tb) lead compounds that are structurally similar to purine bases and nucleosides. The goal of this grant proposal is to understand the metabolism of these agents in M. tb and human cells in order to identify the basis for their selective activity. These studies should lead to a thorough understanding of the substrate characteristics of key M. tb purine salvage enzymes. Much is known about the substrate requirements of human enzymes involved in purine metabolism, because of the considerable effort to develop antitumor nucleoside analogs. However, very little is known about the substrate characteristics of purine metabolizing enzymes in M. tb. The proposed studies should remedy this deficiency, and the information gained will be useful in the rational design and development of new agents based on metabolic differences in purine metabolism between humans and M. tb. In our preliminary data we have identified a metabolic difference between M. tb and human purine metabolism that could be involved in the selective activation in M. tb of certain adenosine analogs. However, further work is necessary to completely characterize the mechanism of action of these and other agents. The proposed specific aims to accomplish these goals are: (1) characterization of the metabolism and mechanism of action of adenosine analogs in intact M. tb; (2) isolation and characterization of purine salvage enzymes from M. tb and human sources; (3) design and synthesis of adenosine analogs selective for M. tb; (4) design and synthesis of a combinatorial library of 2 and 6-substituted purities; (5) preliminary biochemical evaluation of compounds synthesized in aim 4; and (6) evaluation of compounds for anti-M. tb activity and toxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043241-03
Application #
6341712
Study Section
Special Emphasis Panel (ZRG5-AARR-1 (03))
Program Officer
Laughon, Barbara E
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$400,369
Indirect Cost
Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205
Buckoreelall, Kajal; Sun, Yanjie; Hobrath, Judith V et al. (2012) Identification of Rv0535 as methylthioadenosine phosphorylase from Mycobacterium tuberculosis. Tuberculosis (Edinb) 92:139-47
Buckoreelall, Kajal; Wilson, Landon; Parker, William B (2011) Identification and characterization of two adenosine phosphorylase activities in Mycobacterium smegmatis. J Bacteriol 193:5668-74
Long, Mary C; Shaddix, Sue C; Moukha-Chafiq, Omar et al. (2008) Structure-activity relationship for adenosine kinase from Mycobacterium tuberculosis II. Modifications to the ribofuranosyl moiety. Biochem Pharmacol 75:1588-600
Long, Mary C; Allan, Paula W; Luo, Mei-Zhen et al. (2007) Evaluation of 3-deaza-adenosine analogues as ligands for adenosine kinase and inhibitors of Mycobacterium tuberculosis growth. J Antimicrob Chemother 59:118-21
Parker, William B; Long, Mary C (2007) Purine metabolism in Mycobacterium tuberculosis as a target for drug development. Curr Pharm Des 13:599-608
Long, Mary C; Parker, William B (2006) Structure-activity relationship for nucleoside analogs as inhibitors or substrates of adenosine kinase from Mycobacterium tuberculosis. I. Modifications to the adenine moiety. Biochem Pharmacol 71:1671-82
Wang, Yimin; Long, Mary C; Ranganathan, Senthil et al. (2005) Overexpression, purification and crystallographic analysis of a unique adenosine kinase from Mycobacterium tuberculosis. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:553-7
Parker, William B; Barrow, Esther W; Allan, Paula W et al. (2004) Metabolism of 2-methyladenosine in Mycobacterium tuberculosis. Tuberculosis (Edinb) 84:327-36
Long, Mary C; Escuyer, Vincent; Parker, William B (2003) Identification and characterization of a unique adenosine kinase from Mycobacterium tuberculosis. J Bacteriol 185:6548-55
Chen, Chih-Kuang; Barrow, Esther W; Allan, Paula W et al. (2002) The metabolism of 2-methyladenosine in Mycobacterium smegmatis. Microbiology 148:289-95

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