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Friday, 05 May 2017 09:24

Paper 2017_05

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Depleting Mycobacterium tuberculosis of the transcription termination factor Rho causes pervasive transcription and rapid death.

Authors: Laure Botella, Julien Vaubourgeix, Jonathan Livny & Dirk Schnappinger


Abstract: Rifampicin, which inhibits bacterial RNA polymerase, provides one of the most effective treatments for tuberculosis. Inhibition of the transcription termination factor Rho is used to treat some bacterial infections, but its importance varies across bacteria. Here we show that Rho of Mycobacterium tuberculosis functions to both define the 3' ends of mRNAs and silence substantial fragments of the genome. Brief inactivation of Rho affects over 500 transcripts enriched for genes of foreign DNA elements and bacterial virulence factors. Prolonged inactivation of Rho causes extensive pervasive transcription, a genome-wide increase in antisense transcripts, and a rapid loss of viability of replicating and non-replicating M. tuberculosis in vitro and during acute and chronic infection in mice. Collectively, these data suggest that inhibition of Rho may provide an alternative strategy to treat tuberculosis with an efficacy similar to inhibition of RNA polymerase.



Nat Commun. 2017 Mar 28;8:14731. doi: 10.1038/ncomms14731.



Appropriate termination of RNA synthesis is a prerequisite for bacterial viability. The RNA/DNA helicase/translocase Rho is the main termination factor for transcription termination, absent from the genome of eukaryotes and can be selectively inhibited by bicyclomycin (Link). In this study Schnappinger and his team used conditional knockdown mutants to show that Rho from MTB (link) is important for silencing gene expression including insertion elements and phages as well as of PE/PPE genes. More importantly they found that Rho depletion led to a widespread increase of antisense transcription leading to bactericidal effects in vitro as well as in vivo effectively eliminating M. tuberculosis during acute and chronic mouse infection. Rho depletion could also eradicate class II persisters. Currently bicyclomycin is not very active and poorly absorbed when given orally, but targeting Rho from MTB for drug development is promising.


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