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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-A (02))
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Peavy, Hannah H
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New York University
Schools of Medicine
New York
United States
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Bode, Nadine J; Darwin, K Heran (2014) The Pup-Proteasome System of Mycobacteria. Microbiol Spectr 2:
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Wang, Tao; Darwin, K Heran; Li, Huilin (2010) Binding-induced folding of prokaryotic ubiquitin-like protein on the Mycobacterium proteasomal ATPase targets substrates for degradation. Nat Struct Mol Biol 17:1352-7

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