This grant (No. 1 U19 AI38087-01) is a multi-component, U-19 Cooperative Agreement and represents a multi-disciplinary, multiorganizational focus which is applicable tot eh cell walls of mycobacterium tuberculosis and other opportunistic mycobacterioses. Project 1 (Colo.State Univ., Univ. Newcastle, U.K., Univ. Wis., Madison; P.J. Brennan, PL; G.S. Besra, CoPL) (Biochemistry of Mycolate Synthesis) proposes to isolate and identify the enzymes and co-factors responsible for mycolate synthesis and deposition, develop assays to screen for antagonists and to synthesize potential antagonists. Project 2 (Colo. State Univ; J.T. Belisle, PL) (Genetic Analysis of Mycolic Acid Synthese) proposes to clone, sequence and produce in recombinant form the key enzymes for additional study of structural activity relationships and generate knock-out and temperature-sensitive mutants in mycolate synthesis. Project 3 (SmithKline Beecham, U.K., I. Chopra, PL) (The Mycobacterial Cell Envelope; A Target for Novel Drugs Against Tuberculosis and Related Diseases) presents an on-going and developmental program by a major pharmaceutical company for identification of antagonists to mycolic acid synthesis and whole cell growth. Project 4 (Colo, State Univ.; J.M. Inamine, PL) (Genetics of Arabinan and LAM Biosynthesis in Mycobacteria) proposes to identify the genes encoding ethambutol resistance and the synthesis of the major cell wall polysaccharides. Project 5 (Univ. Wis., Madison; Univ. Newcastle, U.K., K. Takayama, PL; I.C. Hancock, Co-PL) (Biosynthesis of the Linkage Region, LAM and AG of Mycobacterium) proposes to define the pathways leading to synthesis of linker-region arabinogalactan and lipoarabinomannan with a view to developing screens suitable for identification of inhibitors and thereby attracting an industrial partner to this aspect of the research. Core A (P.J. Brennan, PI and CL) is for administration of the consortium, and Core B (I.M. Orme, CL) provides a facility for in vitro screening of new drugs.