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

TITLE=Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.02895

DOI=10.3389/fmicb.2018.02895

ISSN=1664-302X

ABSTRACT=<p>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 <italic>rpoA</italic> or <italic>rpoC</italic> have been proposed to compensate for this fitness cost due to <italic>rpoB</italic> mutation in rifampicin-resistant <italic>Mycobacterium tuberculosis</italic> 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 <italic>rpoB</italic> or dual mutations in <italic>rpoB</italic>/<italic>rpoC</italic>, as well as 3 rifampin-susceptible clinical isolates, trying to prove the potential compensatory effect of <italic>rpoC</italic> by transcriptomic alteration. In rifampin-free conditions, <italic>rpoC</italic> mutation was associated with <italic>M. tuberculosis</italic> 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 <italic>M. tuberculosis</italic> isolates, <italic>rpoC</italic> mutations were associated with the upregulation of the oxidative phosphorylation machinery, which was inhibited in the <italic>rpoB</italic> 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 <italic>rpoC</italic> mutation may compensate for the fitness defect of rifampicin-resistant <italic>M. tuberculosis</italic> by altering gene expression in response to rifampin exposure.</p>