Thoughtful evaluation of new agents alone and in combination in a murine model of tuberculosis will lead to improved understanding of their potential efficacy for treatment of human disease. This knowledge will facilitate more appropriate and cost effective human trial design. New agents (capreomycin analogs, pyrazinamide and nicotinamide analogs, Dr. Welch, Scientific Core A; isoniazid analogs and thiosemicarbazones, Dr. J. Fung-Tome, Project 1; and inhibitors of rhamnose and galactose metabolism, Dr. Reynolds, Project 5) will initially be evaluated in dose response studies in comparison to isoniazid (INH) and/or rifampin (RIF) using a murine test system. Subsequently promising agents will be studied in combination with a long lasting rifamycin (rifapentine or KRM 1648) in comparison to INH and RIF to determine their sterilizing efficacy and potential for ultra-short course (less than or equal to 4 month) chemotherapy regimens. A similar approach will be utilized to develop an effective regimen for chemotherapy of multidrug resistant tuberculosis. There is a need for shorter duration preventive therapy regimens. A murine model will be developed to evaluate agents for their potential activity for preventive therapy (i.e., activity against quiescent or dormant M. tuberculosis). Metronidazole and capreomycin analogs will be studied in the preventive therapy model after initial in vitro evaluation (Dr. Heifets, Project 1). Pyrazinamide and nicotinamide analogs (Dr. Welch) as well as other new agents (Dr. Reynolds and Dr. J. Fung-Tome) will be evaluated in the same model(s) if preliminary in vitro studies demonstrate promising activity. These agents will be tested alone and in combination with a rifamycin in comparison with INH alone and INH in combination with RIF in combination with RIF.
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