Tuberculosis is second behind AIDS, as the World's most deadly microbial infection. However, a major fraction of AIDS patients die of mycobacterial infections, including TB. The TB problem is aggravated by the growing prevalence of drug-resistant TB, and especially multi-drug resistant (MDR) TB, which cannot be treated with the front-line antibiotics for Mycobacterium tuberculosis. It is therefore important that targets be identified for development of new drugs for treatment of MDR TB. Suitable target enzymes should have biochemical functions essential for mycobacteria but have no similar function in mammals, making it likely that drugs can be developed that will not lead to adverse reactions in humans. They must have well-defined assays suitable for screening of potential drugs. The proposed research elucidates the biochemistry associated with the production and utilization of the antioxidant thiol known as mycothiol. Mycothiol is produced only by mycobacteria, and other actinomycetes, and is not found in animals. The key genes for mycothiol biosynthesis have recently been identified and provide important potential novel drug targets. Studies of mycothiol-deficient mutants indicate that mycothiol metabolism is involved in protecting against oxidative damage and in the detoxification of antibiotics, including a first-line TB drug. Although not essential for the laboratory culture of the model organism Mycobacterium smegmatis, it has been shown that mycothiol is essential for aerobic growth of M. tuberculosis. The present studies will determine the extent to which mycothiol is essential for survival of dormant M. tuberculosis, will define the biochemistry involved in the first key step of mycothiol biosynthesis, and will identify compounds capable of inhibiting mycothiol biosynthesis in mycobacteria. Methods used include new analytical and enzyme assays developed in these laboratories as well as established protocols in biochemistry and molecular biology. The results obtained will provide a key test of the suitability of mycothiol biosynthesis as a target for new TB drugs and will elaborate the biochemistry of a novel class of thiol important to a broad range of soil microorganisms, including most antibiotic-producing bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049174-05
Application #
6893419
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Laughon, Barbara E
Project Start
2000-08-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
5
Fiscal Year
2005
Total Cost
$304,000
Indirect Cost
Name
University of California San Diego
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Newton, Gerald L; Rawat, Mamta; La Clair, James J et al. (2009) Bacillithiol is an antioxidant thiol produced in Bacilli. Nat Chem Biol 5:625-7
Johnson, Todd; Newton, Gerald L; Fahey, Robert C et al. (2009) Unusual production of glutathione in Actinobacteria. Arch Microbiol 191:89-93
Newton, Gerald L; Jensen, Paul R; Macmillan, John B et al. (2008) An N-acyl homolog of mycothiol is produced in marine actinomycetes. Arch Microbiol 190:547-57