Mycobacterium tuberculosis remains one of the most devastating human infectious diseases, causing two million deaths annually and latently infecting a third of the world's population. As an intracellular pathogen adapted to long-term survival, M. tuberculosis has evolved mechanisms to resist killing by host antimicrobial pathways. Targeting those resistance mechanisms has recently emerged as a powerful new approach to treating M. tuberculosis infection by enhancing the host's ability to eradicate the bacteria. However, the full repertoire of mycobacterial resistance genes is not known, and expanding this knowledge base provides additional avenues for the development of new drugs. We demonstrated the M. tuberculosis induces an enzyme, heme oxygenase, that produces carbon monoxide (CO) gas, and that M. tuberculosis both adapts to and resists killing by CO. We hypothesized that M. tuberculosis evolved genes for CO resistance, and our preliminary data indicate that M. tuberculosis encodes one such gene that when mutated results in attenuated virulence. We will apply metabolomic, transcriptomic, proteomic, and biochemical approaches to determine the function of the newly discovered CO resistance protein. Thus, in the proposed research we will (1) identify the molecular mechanism of CO resistance, (2) determine the interacting partners of the CO resistance gene and their role in CO resistance and (3) characterize the pathogenic effects of mutants in the CO resistance gene and its interacting partners. The proposed work will extend the current knowledge on M. tuberculosis's antimicrobial resistance mechanisms and reveal a novel microbial survival strategy.

Public Health Relevance

Tuberculosis is a major human pathogen, accounting for significant morbidity and mortality worldwide. Work outlined in this proposal will investigate a novel mechanism that allows M. tuberculosis to survive and persist within humans. We expect that this work will help identify new potential drug targets for the treatment of tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI099439-02
Application #
8554358
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Lacourciere, Karen A
Project Start
2012-09-27
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$373,650
Indirect Cost
$138,650
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Zacharia, Vineetha M; Manzanillo, Paolo S; Nair, Vidhya R et al. (2013) cor, a novel carbon monoxide resistance gene, is essential for Mycobacterium tuberculosis pathogenesis. MBio 4:e00721-13
Manzanillo, Paolo S; Ayres, Janelle S; Watson, Robert O et al. (2013) The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501:512-6
Sampaio, Elizabeth P; Hsu, Amy P; Pechacek, Joseph et al. (2013) Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol 131:1624-34