Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI038087-01
Application #
2075012
Study Section
Special Emphasis Panel (SRC (74))
Project Start
1995-08-01
Project End
1999-07-31
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Colorado State University-Fort Collins
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
112617480
City
Fort Collins
State
CO
Country
United States
Zip Code
80523

  Publications

Gibson, Kevin J C; Gilleron, Martine; Constant, Patricia et al. (2003) Structural and functional features of Rhodococcus ruber lipoarabinomannan. Microbiology 149:1437-45
Phetsuksiri, Benjawan; Jackson, Mary; Scherman, Hataichanok et al. (2003) Unique mechanism of action of the thiourea drug isoxyl on Mycobacterium tuberculosis. J Biol Chem 278:53123-30
Kremer, Laurent; Gurcha, Sudagar S; Bifani, Pablo et al. (2002) Characterization of a putative alpha-mannosyltransferase involved in phosphatidylinositol trimannoside biosynthesis in Mycobacterium tuberculosis. Biochem J 363:437-47
Nigou, Jerome; Besra, Gurdyal S (2002) Characterization and regulation of inositol monophosphatase activity in Mycobacterium smegmatis. Biochem J 361:385-90
Cooper, Howard N; Gurcha, Sudagar S; Nigou, Jerome et al. (2002) Characterization of mycobacterial protein glycosyltransferase activity using synthetic peptide acceptors in a cell-free assay. Glycobiology 12:427-34
Kremer, Laurent; Dover, Lynn G; Carrere, Severine et al. (2002) Mycolic acid biosynthesis and enzymic characterization of the beta-ketoacyl-ACP synthase A-condensing enzyme from Mycobacterium tuberculosis. Biochem J 364:423-30
Gurcha, Sudagar S; Baulard, Alain R; Kremer, Laurent et al. (2002) Ppm1, a novel polyprenol monophosphomannose synthase from Mycobacterium tuberculosis. Biochem J 365:441-50
Nigou, Jerome; Besra, Gurdyal S (2002) Cytidine diphosphate-diacylglycerol synthesis in Mycobacterium smegmatis. Biochem J 367:157-62
Larsen, Michelle H; Vilcheze, Catherine; Kremer, Laurent et al. (2002) Overexpression of inhA, but not kasA, confers resistance to isoniazid and ethionamide in Mycobacterium smegmatis, M. bovis BCG and M. tuberculosis. Mol Microbiol 46:453-66
Hancock, Ian C; Carman, Stephen; Besra, Gurdyal S et al. (2002) Ligation of arabinogalactan to peptidoglycan in the cell wall of Mycobacterium smegmatis requires concomitant synthesis of the two wall polymers. Microbiology 148:3059-67

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