The emergence of multidrug resistant forms of tuberculosis (TB), as well as the rapid course of infection and poor prognosis for HIV patients coinfected with TB, underscores the need for more effective utilization of clinically available antitubercular agents as well as new, more selective agents directed against biochemical targets specific to the mycobacterium. Inhibitors of cell wall biosynthesis have been a mainstay of modern antitubercular chemotherapy as evidenced by the accepted mechanisms of action of the clinically effective agents isoniazid, ethambutol and ethionamide. Recent advances in the characterization of the mycobacterial cell wall have led to the identification of a vast array of highly unique biochemical targets that could lead to new, potent, and selective antitubercular agents. With the goal of developing such new agents, this project will focus on design and synthesis of novel inhibitors of the biogenesis and utilization of two mycobacterial cell wall saccharides not found in humans, D-galactofuranose (galf) and L-rhamnopyranose (rhap). Specifically, we propose to synthesize analogs of thymidine-diphosphate- rhap as well as specific rhap containing di- and trisaccharide derivatives as inhibitors of rhamnose metabolism and incorporation. We also propose to synthesize analogs of uridine-diphosphate-galf and galf containing di- and trisaccharides as inhibitors of galactofuranose metabolism. Target compounds will be supplied to Dr. Leonid Heifets (Principal Investigator and Leader of Project 1) for in vitro assays. Selected active compounds as determined from the in vitro assays will be tested in vivo in the murine model in Project 2 (Dr. Michael Cynamon, Project Leader). All compounds will be tested as well in the cell free assays available in Project 4 (Dr. Michael McNeil, Project Leader). Biological data from Projects 1, 2, and 4 will direct now compound design in order to enhance drug activity and bioavailability.

Project Start
1999-06-01
Project End
2001-05-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206
Chung, Woo Jin; Kornilov, Andrei; Brodsky, Benjamin H et al. (2008) Inhibition of M. tuberculosis in vitro in monocytes and in mice by aminomethylene pyrazinamide analogs. Tuberculosis (Edinb) 88:410-9
Zhao, Kake; Lim, Dong Sung; Funaki, Takashi et al. (2003) Inhibition of dipeptidyl peptidase IV (DPP IV) by 2-(2-amino-1-fluoro-propylidene)-cyclopentanecarbonitrile, a fluoroolefin containing peptidomimetic. Bioorg Med Chem 11:207-15
Scherman, Michael S; Winans, Katharine A; Stern, Richard J et al. (2003) Drug targeting Mycobacterium tuberculosis cell wall synthesis: development of a microtiter plate-based screen for UDP-galactopyranose mutase and identification of an inhibitor from a uridine-based library. Antimicrob Agents Chemother 47:378-82
Pathak, A K; Pathak, V; Khare, N K et al. (2001) Synthesis of disaccharides related to the mycobacterial arabinogalactan. Carbohydr Lett 4:117-22
Ma, Y; Stern, R J; Scherman, M S et al. (2001) Drug targeting Mycobacterium tuberculosis cell wall synthesis: genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob Agents Chemother 45:1407-16
Brown, J R; Field, R A; Barker, A et al. (2001) Synthetic mannosides act as acceptors for mycobacterial alpha1-6 mannosyltransferase. Bioorg Med Chem 9:815-24
Shoen, C M; DeStefano, M S; Cynamon, M H (2000) Durable cure for tuberculosis: rifalazil in combination with isoniazid in a murine model of Mycobacterium tuberculosis infection. Clin Infect Dis 30 Suppl 3:S288-90
Shoen, C M; Chase, S E; DeStefano, M S et al. (2000) Evaluation of rifalazil in long-term treatment regimens for tuberculosis in mice. Antimicrob Agents Chemother 44:1458-62
Lenaerts, A M; Chase, S E; Cynamon, M H (2000) Evaluation of rifalazil in a combination treatment regimen as an alternative to isoniazid-rifampin therapy in a mouse tuberculosis model. Antimicrob Agents Chemother 44:3167-8
Cynamon, M H; Zhang, Y; Harpster, T et al. (1999) High-dose isoniazid therapy for isoniazid-resistant murine Mycobacterium tuberculosis infection. Antimicrob Agents Chemother 43:2922-4

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