Interaction of CarD with RNA Polymerase Mediates Mycobacterium tuberculosis Viability, Rifampin Resistance, and Pathogenesis

Weiss, LA, Harrison PG, Nickels BE, Glickman MS, Campbell EA, Darst SA, Stallings CL.  2012.  

Journal:

J Bacteriol

Volume Number:

194

Pages:

5621-5631

Abstract:

Mycobacterium tuberculosis infection continues to cause substantial human suffering. New chemotherapeutic strategies, which require insight into the pathways essential for M. tuberculosis pathogenesis, are imperative. We previously reported that depletion of the CarD protein in mycobacteria compromises viability, resistance to oxidative stress and fluoroquinolones, and pathogenesis. CarD associates with the RNA polymerase (RNAP), but it has been unknown which of the diverse functions of CarD are mediated through the RNAP; this question must be answered to understand the CarD mechanism of action. Herein, we describe the interaction between the M. tuberculosis CarD and the RNAP beta subunit and identify point mutations that weaken this interaction. The characterization of mycobacterial strains with attenuated CarD/RNAP beta interactions demonstrates that the CarD/RNAP beta association is required for viability and resistance to oxidative stress but not for fluoroquinolone resistance. Weakening the CarD/RNAP beta interaction also increases the sensitivity of mycobacteria to rifampin and streptomycin. Surprisingly, depletion of the CarD protein did not affect sensitivity to rifampin. These findings define the CarD/RNAP interaction as a new target for chemotherapeutic intervention that could also improve the efficacy of rifampin treatment of tuberculosis. In addition, our data demonstrate that weakening the CarD/RNAP beta interaction does not completely phenocopy the depletion of CarD and support the existence of functions for CarD independent of direct RNAP binding.

Notes:

Weiss, Leslie AHarrison, Phillip GNickels, Bryce EGlickman, Michael SCampbell, Elizabeth ADarst, Seth AStallings, Christina LUnited StatesJournal of bacteriologyJ Bacteriol. 2012 Oct;194(20):5621-31. Epub 2012 Aug 17.

Related External URL:

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22904282
Citation:
Weiss, LA, Harrison PG, Nickels BE, Glickman MS, Campbell EA, Darst SA, Stallings CL.  2012.  Interaction of CarD with RNA Polymerase Mediates Mycobacterium tuberculosis Viability, Rifampin Resistance, and Pathogenesis. J Bacteriol. 194:5621-5631.