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.
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