Tuberculosis, the disease arising from infection by Mycobacterium tuberculosis, kills nearly three million people worldwide each year making it the single most lethal bacterial disease. The recent resurgence of many mycobacterial diseases, including tuberculosis, has prompted interest in developing new antimycobacterial agents. The great urgency of this task has been underscored by the emergence of M. tuberculosis strains resistant to many of the currently effective antibiotics. The long-term objective of this project is the identification of inhibitors of mycobacterial cell wall biosynthesis. This proposal focuses on the enzymes involved in the biogenesis of the D- arabinofuranose polymers which are critical components of two cell wall polysaccharides, arabinogalactan and lipoarabinomannan. Inhibitors of the arabinosyltransferases that assemble these glycans are expected to be potent antimycobacterial agents, and these enzymes are ideal targets for antibiotic action because furanose oligosaccharides are unknown in humans. We propose to synthesize a series of oligosaccharides and oligosaccharide analogs and evaluate them as substrates or inhibitors of mycobacterial arabinosyltransferases. These compounds will be invaluable in not only biosynthetic studies, but also as lead compounds for drug development.
The specific aims of this proposal are: 1.) The synthesis of arabinofuranosyl oligosaccharides found as constituents of mycobacterial cell wall polysaccharides; 2.) The synthesis of a series of rationally-designed O-glycoside analogs of the oligosaccharides prepared in Specific Aim 1; 3.) The design and synthesis of C-glycoside and carbocyclic arabinofuranoside mimics; 4.) The design and synthesis of C-phosphonate analogs of the activated biological donor of arabinofuranose; 5.) The evaluation of these synthetic glycans as substrates or inhibitors of mycobacterial cell wall biosynthesis.
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