Continuance is requested of a historical, MERIT-designated award responsible for much of present-day understanding of the architecture and biogenesis of mycobacterial cell walls. The new thrust is the development of drug targets/screens to counteract multiple drug resistant TB and, tangentially, aid in definition of mechanisms of disease pathogenesis. The experimental approach centers on four major topics: 1. Knowledge of the pathways of linker unit (LU), arabinogalactan (AG) and lipoarabinomannan (LAM) biosynthesis warrants identification and production of the relevant glycosyltransferases through synthesis of sugar-donors, neoglycolipid-acceptors and photoaffinity probes and through genome database searches, and application of the results to cascade, acceptor-donor and single-enzyme high-throughput screens to assess compound, combinatorial and natural product libraries in conjunction with GlaxoWellcome. 2. The unique structures of the mycobacterial polyprenyl-P carriers and expected unique specificity of the isoprenol initiating reactions warrants analysis of these pathways in terms of the worth of such fundamental information and its possible application in drug development. 3. The extreme paucity of information on the peptidoglycan of M. tuberculosis invites an examination of basic structure and biosynthesis, assessment of conformation/ solution structure in the contexts of AG and cell wall proper by means of high resolution NMR, and definition of extra-membranous events such as polymerization, cross-linking and linkage to AG. 4. The recent recognition of the nature of the mycolic acid carrier, and the mycolyltransferase enzyme and the mechanism of Claisen condensation calls for an enzymatic and genetic approach to defining the mechanisms and essentiality of the terminal stages of mycolic acid synthesis, transport and deposition through recourse of drug-resistant genes to some novel mycolic acid antagonists, and """"""""knock-out"""""""" mutagenesis of these and other genes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BM-1 (03))
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Ginsberg, Ann M
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Colorado State University-Fort Collins
Schools of Veterinary Medicine
Fort Collins
United States
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