Abstract

Mycobacterial cell wall synthesis is a potential point of intervention in mycobacterial pathogenesis. The investigators will design and synthesize inhibitors of mycobacterial enzymes rhap and galf (neither are found in mammalian cells). Specifically, glycosyl donor and acceptor analogs of mycobacterial rhamnosyl- galactosyltransferases that utilize nucleoside diphosphate sugar donors UDP-galactofuranose and TDP-rhamnopyranose. Also, the investigators will make disaccharides that bind and inhibit in the acceptor site of the sugar transferases. These compounds will be screened in vitro using a broth dilution assay and cell-free assay transferase. Selected active compounds will be screened in vitro and in vivo in a macrophage assay and a murine TB model, respectively.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045317-04
Application #
6534152
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (01))
Program Officer
Near, Karen A
Project Start
1999-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2002
Total Cost
$431,232
Indirect Cost

  Institution

Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205

  Publications

Pathak, Ashish K; Pathak, Vibha; Seitz, Lainne E et al. (2013) 6-Oxo and 6-thio purine analogs as antimycobacterial agents. Bioorg Med Chem 21:1685-95
Pathak, Ashish K; Pathak, Vibha; Suling, William J et al. (2009) Synthesis of deoxygenated alpha(1-->5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis. Bioorg Med Chem 17:872-81
Pathak, Ashish K; Pathak, Vibha; Seitz, Lainne et al. (2007) Disaccharide analogs as probes for glycosyltransferases in Mycobacterium tuberculosis. Bioorg Med Chem 15:5629-50
Pathak, Ashish K; Pathak, Vibha; Riordan, James R et al. (2007) Synthesis of symmetrical C- and pseudo-symmetrical O-linked disaccharide analogs for arabinosyltransferase inhibitory activity in Mycobacterium tuberculosis. Bioorg Med Chem Lett 17:4527-30
Reynolds, Robert C; Campbell, Shiela R; Fairchild, Ralph G et al. (2007) Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation. J Med Chem 50:3283-9
Pathak, Ashish K; Pathak, Vibha; Seitz, Lainne E et al. (2004) Antimycobacterial agents. 1. Thio analogues of purine. J Med Chem 47:273-6
Pathak, Ashish K; Pathak, Vibha; Riordan, James M et al. (2004) Synthesis of mannopyranose disaccharides as photoaffinity probes for mannosyltransferases in Mycobacterium tuberculosis. Carbohydr Res 339:683-91
Rose, Jerry D; Maddry, Joseph A; Comber, Robert N et al. (2002) Synthesis and biological evaluation of trehalose analogs as potential inhibitors of mycobacterial cell wall biosynthesis. Carbohydr Res 337:105-20
Pathak, Ashish K; Pathak, Vibha; Suling, William J et al. (2002) Studies on n-octyl-5-(alpha-D-arabinofuranosyl)-beta-D-galactofuranosides for mycobacterial glycosyltransferase activity. Bioorg Med Chem 10:923-8
Seitz, Lainne E; Suling, William J; Reynolds, Robert C (2002) Synthesis and antimycobacterial activity of pyrazine and quinoxaline derivatives. J Med Chem 45:5604-6

Showing the most recent 10 out of 14 publications