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.
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.
|Jastrab, Jordan B; Samanovic, Marie I; Copin, Richard et al. (2017) Loss-of-Function Mutations in HspR Rescue the Growth Defect of a Mycobacterium tuberculosis Proteasome Accessory Factor E (pafE) Mutant. J Bacteriol 199:|
|Becker, Samuel H; Darwin, K Heran (2017) Bacterial Proteasomes: Mechanistic and Functional Insights. Microbiol Mol Biol Rev 81:|
|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, Ond?ej et al. (2015) Proteasomal control of cytokinin synthesis protects Mycobacterium tuberculosis against nitric oxide. Mol Cell 57:984-94|
|Darwin, K Heran (2015) Mycobacterium tuberculosis and Copper: A Newly Appreciated Defense against an Old Foe? J Biol Chem 290:18962-6|
|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|
|Shi, Xiaoshan; Festa, Richard A; Ioerger, Thomas R et al. (2014) The copper-responsive RicR regulon contributes to Mycobacterium tuberculosis virulence. MBio 5:|
|Bode, Nadine J; Darwin, K Heran (2014) The Pup-Proteasome System of Mycobacteria. Microbiol Spectr 2:|
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