Tuberculosis kills about 2 million people globally every year. A key defense against Mycobacterium tuberculosis (Mtb) infections is the production of nitric oxide (NO) by macrophages. Although NO controls Mtb growth, it rarely sterilizes the bacterium from the host, suggesting Mtb has mechanisms to resist NO toxicity. The Mtb proteasome is one such mechanism that is required for resistance to NO. The proteasome is a multi-subunit, barrel shaped complex that degrades proteins and is conserved in all domains of life. In addition to providing resistance to NO, the Mtb proteasome is necessary to cause lethal infections in mice. We are currently trying to understand how proteolysis is linked to NO resistance as well as protecting Mtb against other host defenses. We have made two substantial discoveries during our studies: the Mtb proteasome regulates (1) the stability of an enzyme predicted to catalyze the production of cytokinins, the activity of which is linked to NO resistance;and (2) the expression of a novel copper-resistance regulon. We are working to characterize how the proteasome participates in these pathways, the knowledge of which may help us better understand the pathogenesis of one of the world's deadliest diseases.

Public Health Relevance

Tuberculosis kills nearly 2 million people annually. Tuberculosis therapy takes 6-9 months, a problem that leads to decreased compliance for taking antibiotics and increased chances of developing drug-resistance. The rise of extensively drug resistant (XDR) strains of M. tuberculosis is a public concern, thus the identification of specific pathways in Mycobacterium tuberculosis that could be targeted by new drugs is of great interest.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092774-07
Application #
8646960
Study Section
Special Emphasis Panel (ZRG1-IDM-A (02))
Program Officer
Peavy, Hannah H
Project Start
2007-09-20
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$415,275
Indirect Cost
$170,275
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Samanovic, Marie I; Darwin, K Heran (2016) Game of 'Somes: Protein Destruction for Mycobacterium tuberculosis Pathogenesis. Trends Microbiol 24:26-34
Nowicka, Urszula; Hoffman, Morgan; Randles, Leah et al. (2016) Mycobacterium tuberculosis copper-regulated protein SocB is an intrinsically disordered protein that folds upon interaction with a synthetic phospholipid bilayer. Proteins 84:193-200
Samanovic, Marie I; Tu, Shengjiang; Novák, Ondřej et al. (2015) Proteasomal control of cytokinin synthesis protects Mycobacterium tuberculosis against nitric oxide. Mol Cell 57:984-94
Shi, Xiaoshan; Darwin, K Heran (2015) Copper homeostasis in Mycobacterium tuberculosis. Metallomics 7:929-34
Jastrab, Jordan B; Darwin, K Heran (2015) Bacterial Proteasomes. Annu Rev Microbiol 69:109-27
Darwin, K Heran (2015) Mycobacterium tuberculosis and Copper: A Newly Appreciated Defense against an Old Foe? J Biol Chem 290:18962-6
Bode, Nadine J; Darwin, K Heran (2014) The Pup-Proteasome System of Mycobacteria. Microbiol Spectr 2:
Bode, Nadine J; Darwin, K Heran (2014) The Pup-Proteasome System of Mycobacteria. Microbiol Spectr 2:
Shi, Xiaoshan; Festa, Richard A; Ioerger, Thomas R et al. (2014) The copper-responsive RicR regulon contributes to Mycobacterium tuberculosis virulence. MBio 5:
Samanovic, Marie I; Li, Huilin; Darwin, K Heran (2013) The pup-proteasome system of Mycobacterium tuberculosis. Subcell Biochem 66:267-95

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