Transcriptional approach for decoding the mechanism of rpoC compensatory mutations for the fitness cost in rifampicin-resistant Mycobacterium tuberculosis

Zhihong Xu, Aiping Zhou, Jiawei Wu, Aiwu Zhou, Jun Li, Shulin Zhang, Wenjuan Wu, Petros C. Karakousis, Yu Feng Yao

Research output: Contribution to journalArticle

Abstract

Multidrug-resistant tuberculosis (TB), defined as TB resistant to the two first-line drugs, isoniazid and rifampin, is a serious challenge to global TB eradication efforts. Although mutations in rpoA or rpoC have been proposed to compensate for this fitness cost due to rpoB mutation in rifampicin-resistant Mycobacterium tuberculosis mutants, whether the compensatory effect exists and the underlying mechanisms of compensation remain unclear. Here, we used RNA sequencing to investigate the global transcriptional profiles of 6 rifampin-resistant clinical isolates with either single mutation in rpoB or dual mutations in rpoB/rpoC, as well as 3 rifampin-susceptible clinical isolates, trying to prove the potential compensatory effect of rpoC by transcriptomic alteration. In rifampin-free conditions, rpoC mutation was associated with M. tuberculosis upregulation of ribosomal protein-coding genes, dysregulation of growth-related essential genes and balancing the expression of arginine and glutamate synthesis-associated genes. Upon rifampin exposure of M. tuberculosis isolates, rpoC mutations were associated with the upregulation of the oxidative phosphorylation machinery, which was inhibited in the rpoB single mutants, as well as stabilization of the expression of rifampin-regulated essential genes and balancing the expression of genes involved in metabolism of sulfur-containing amino acids. Taken together, our data suggest that rpoC mutation may compensate for the fitness defect of rifampicin-resistant M. tuberculosis by altering gene expression in response to rifampin exposure.

Original languageEnglish (US)
Article number2895
JournalFrontiers in Microbiology
Volume9
Issue numberNOV
DOIs
StatePublished - Nov 30 2018

Keywords

  • Fitness cost
  • Mycobacterium tuberculosis
  • RNA sequence
  • Rifampicin resistance
  • RpoC mutation

ASJC Scopus subject areas

  • Microbiology
  • Microbiology (medical)

Fingerprint Dive into the research topics of 'Transcriptional approach for decoding the mechanism of rpoC compensatory mutations for the fitness cost in rifampicin-resistant Mycobacterium tuberculosis'. Together they form a unique fingerprint.

  • Cite this