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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Parker, Tina M
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State University New York Stony Brook
Schools of Arts and Sciences
Stony Brook
United States
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Lu, Rui; Schaefer, Christin M; Nesbitt, Natasha M et al. (2017) Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis Is Controlled by a Redox-Sensitive Thiol Switch. ACS Infect Dis 3:666-675
Schaefer, Christin M; Lu, Rui; Nesbitt, Natasha M et al. (2015) FadA5 a thiolase from Mycobacterium tuberculosis: a steroid-binding pocket reveals the potential for drug development against tuberculosis. Structure 23:21-33
Lu, Rui; Schmitz, Werner; Sampson, Nicole S (2015) ?-Methyl Acyl CoA Racemase Provides Mycobacterium tuberculosis Catabolic Access to Cholesterol Esters. Biochemistry 54:5669-72
Yang, Meng; Lu, Rui; Guja, Kip E et al. (2015) Unraveling Cholesterol Catabolism in Mycobacterium tuberculosis: ChsE4-ChsE5 ?2?2 Acyl-CoA Dehydrogenase Initiates ?-Oxidation of 3-Oxo-cholest-4-en-26-oyl CoA. ACS Infect Dis 1:110-125
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
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
Slayden, Richard A; Jackson, Mary; Zucker, Jeremy et al. (2013) Updating and curating metabolic pathways of TB. Tuberculosis (Edinb) 93:47-59
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
Wipperman, Matthew F; Yang, Meng; Thomas, Suzanne T et al. (2013) Shrinking the FadE proteome of Mycobacterium tuberculosis: insights into cholesterol metabolism through identification of an ?2?2 heterotetrameric acyl coenzyme A dehydrogenase family. J Bacteriol 195:4331-41
Thomas, Suzanne T; VanderVen, Brian C; Sherman, David R et al. (2011) Pathway profiling in Mycobacterium tuberculosis: elucidation of cholesterol-derived catabolite and enzymes that catalyze its metabolism. J Biol Chem 286:43668-78