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).
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