4 years ago

Whole transcriptome and genomic analysis of extensively drug-resistant Mycobacterium tuberculosis clinical isolates identifies downregulation of ethA as a mechanism of ethionamide resistance.

Pym, Maharaj, de Welzen, Earl, Manson, Eldholm
Genetic based drug susceptibility testing has improved the diagnosis of drug-resistant tuberculosis, but is limited by our lack of knowledge of all resistance mechanisms. Next generation sequencing has assisted in identifying the principal genetic mechanisms of resistance for many drugs, but a significant proportion of phenotypic drug resistance is unexplained genetically. Few studies have formally compared the transcriptome of susceptible and resistant M. tuberculosis We carried out comparative whole genome transcriptomics on extensively drug-resistant (XDR) clinical isolates using RNA-sequencing (RNAseq) to find novel transcriptional mediated mechanisms of resistance. We identified a t-11c promoter mutation that reduces expression of a monooxygenase (EthA) that activates ethionamide. Using a flow-cytometry based reporter assay, we show that reduced transcription of ethA is not due to transcriptional repression by ethR Clinical strains harbouring this mutation were resistant to ethionamide. Other ethA promoter mutations were identified in a global genomic survey of resistant M. tuberculosis strains. These results demonstrate a new mechanism of ethionamide resistance that can cause high-level resistance when combined with other ethionamide resistance conferring mutations. Our study revealed many other genes which were highly up or down regulated in XDR strains, including a toxin-antitoxin module (mazF5mazE5) and tRNAs (leuX and thrU). This suggests more global transcriptional modifications have also occurred in XDR strains that could contribute to resistance or maintaining bacterial fitness.

Publisher URL: http://doi.org/10.1128/AAC.01461-17

DOI: 10.1128/AAC.01461-17

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