TY - JOUR
T1 - Transcriptional approach for decoding the mechanism of rpoC compensatory mutations for the fitness cost in rifampicin-resistant Mycobacterium tuberculosis
AU - Xu, Zhihong
AU - Zhou, Aiping
AU - Wu, Jiawei
AU - Zhou, Aiwu
AU - Li, Jun
AU - Zhang, Shulin
AU - Wu, Wenjuan
AU - Karakousis, Petros C.
AU - Yao, Yu Feng
N1 - Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81361120383, 81772140, and 81830068), the State Key Development Programs for
Publisher Copyright:
Copyright © 2018 Xu, Zhou, Wu, Zhou, Li, Zhang, Wu, Karakousis and Yao.
PY - 2018/11/30
Y1 - 2018/11/30
N2 - 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.
AB - 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.
KW - Fitness cost
KW - Mycobacterium tuberculosis
KW - RNA sequence
KW - Rifampicin resistance
KW - RpoC mutation
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U2 - 10.3389/fmicb.2018.02895
DO - 10.3389/fmicb.2018.02895
M3 - Article
C2 - 30555440
AN - SCOPUS:85057630322
SN - 1664-302X
VL - 9
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
IS - NOV
M1 - 2895
ER -