The World Health Organization estimates that 2 million people die every year from tuberculosis and that 30% of the world's population is infected. Multi-drug resistant organisms are widespread and extensively drug resistant organisms are emerging. New approaches are required to combat these virulent and drug resistant organisms (MDR/XDR TB). The proposed experiments are aimed at characterizing metabolites produced by M. tb using cholesterol as a starting material. The hypothesis is that M. tb transforms cholesterol to hormones that regulate the host immune system. The corresponding enzymatic activities that catalyze hormone synthesis represent new targets for anti-MDR-TB pharmaceutical development.
The aim of this work is to identify candidate immunomodulatory metabolites produced during growth of M. tb on cholesterol and in macrophages in order to drive the identification of the genes and corresponding enzymes responsible for their formation.

Public Health Relevance

The proposed research fits within the targeted research needs of NIAID that seeks the development of new chemotherapeutic agents against MDR/XDR TB. These experiments will provide a basis for discovering the structure of metabolites that regulate the host immune response to TB and guide development of new antibiotics that would be effective against all forms of TB including MDR/XDR TB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI092455-02
Application #
8230485
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Parker, Tina M
Project Start
2011-02-15
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$192,669
Indirect Cost
$67,669
Name
State University New York Stony Brook
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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Wipperman, Matthew F; Sampson, Nicole S; Thomas, Suzanne T (2014) Pathogen roid rage: cholesterol utilization by Mycobacterium tuberculosis. Crit Rev Biochem Mol Biol 49:269-93
Yang, Meng; Guja, Kip E; Thomas, Suzanne T et al. (2014) A distinct MaoC-like enoyl-CoA hydratase architecture mediates cholesterol catabolism in Mycobacterium tuberculosis. ACS Chem Biol 9:2632-45
Thomas, Suzanne T; Sampson, Nicole S (2013) Mycobacterium tuberculosis utilizes a unique heterotetrameric structure for dehydrogenation of the cholesterol side chain. Biochemistry 52:2895-904
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