Rapid progression of tuberculosis in HIV-infected individuals, growing rates of drug-resistance, the need for alternatives to isoniazid for preventive therapy are among the major problems of tuberculosis today. The main goal of this program is to develop new treatment regimens: for ultra- short (3-4 months) intermittent (twice-a-week) administration; against MDR- TB; for preventive therapy in cases of isoniazid-resistance; and against dormant tubercle bacilli largely responsible for relapses of the disease. These goals will be approached by the collaborative effort of four individual projects and one Scientific Core. One of the projects (No. 1) incorporates a team at Bristol-Myers Squibb Company committed to developing new mycolic acid synthesis inhibitors targeted against isoniazid-resistant M. tuberculosis. New molecular targets among the enzymes responsible for the mycobacterial wall synthesis will be developed under Project No. 4 using new cell-free assay systems. Under Project Nos. 4 and 5, inhibitors of these enzymes will be developed into drugs, with special attention to the rhamnose and galactose metabolism inhibitors. Synthesis of two other groups of antimycobacterial agents will be conducted under Scientific Core A: pyrazinamide analogs active against pyrazinamide-resistant strains; and components of capreomycin and other peptide antibiotics targeted against dormant tubercle bacilli. Selection of new drugs will be based on the structure-activity correlations and therefore will require parallel step- by-step testing of their activity, which will be done mostly under Project No. 1. In addition, newly developed in vitro models will be used under Project No. 1 to evaluate the activity of the drugs targeted against dormant bacilli. Development of drugs targeted against MDR-TB requires cross-resistance studies, which will be performed under Project No. 1 (phenotypically). Antimicrobial activity of new drugs, alone and in combinations, will be evaluated in human macrophage and murine models under Project Nos. 1 and 2. According to our current data, a key element of the ultra-short intermittent regimens is a long-lasting rifamycin (rifapentine or kRM-1648), which will be combined with two other agents, either conventional or newly developed. Regimens targeted against MDR-TB will include substitutes for isoniazid, rifampin, pyrazinamide, streptomycin,ethambutol, developed under this program or already available (for example, some quinolones and aminosidine). Regimens targeted against dormant tubercle bacilli will include metronidazole and some peptide antibiotics to be developed under Scientific Core A.
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