The diagnosis of tuberculosis often precedes the diagnosis of AIDS. As HIV-infected patients liver longer due to anti-viral drug therapy and/or prophylaxis against opportunistic infections, mycobacterial infection will likely become more frequent and contribute to morbidity and mortality. Pyrazinamide (PZA), a primary agent in short course regimens for the treatment of tuberculosis, is recognized as an effective sterilizing drug. The effectiveness of such drugs against slowly metabolizing organisms determines the crucial length of therapy required to prevent relapse. The recent observation that capreomycin (CAP) is also active against dormant or semidormant Mycobacterium tuberculosis (MTB) in vitro affords a second synthetic target for the preparation of drugs which potentially could shorten the length of therapy. The major goal of Scientific Core A will be to synthesize two groups of agents effective against dormant and semi- dormant tubercle bacilli: one a group of compounds which may act as potential replacements for pyrazinamide, the other a set of compounds based on capreomycin with activity against dormant mycobacteria which persist under anaerobic conditions. The synthetic materials will be tested under Project 1. Effectiveness of new therapies in macrophage models (project leader - L, Heifets, National Jewish Center, Denver Co.), and Project 2. New Therapies in the murine model (project leader - M. Cynamon, Veterans Administration medical Center Syracuse).

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
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
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
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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