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

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-re...

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Autores principales: Xu, Zhihong, Zhou, Aiping, Wu, Jiawei, Zhou, Aiwu, Li, Jun, Zhang, Shulin, Wu, Wenjuan, Karakousis, Petros C., Yao, Yu-Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283890/
https://www.ncbi.nlm.nih.gov/pubmed/30555440
http://dx.doi.org/10.3389/fmicb.2018.02895
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author Xu, Zhihong
Zhou, Aiping
Wu, Jiawei
Zhou, Aiwu
Li, Jun
Zhang, Shulin
Wu, Wenjuan
Karakousis, Petros C.
Yao, Yu-Feng
author_facet Xu, Zhihong
Zhou, Aiping
Wu, Jiawei
Zhou, Aiwu
Li, Jun
Zhang, Shulin
Wu, Wenjuan
Karakousis, Petros C.
Yao, Yu-Feng
author_sort Xu, Zhihong
collection PubMed
description 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.
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spelling pubmed-62838902018-12-14 Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis Xu, Zhihong Zhou, Aiping Wu, Jiawei Zhou, Aiwu Li, Jun Zhang, Shulin Wu, Wenjuan Karakousis, Petros C. Yao, Yu-Feng Front Microbiol Microbiology 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. Frontiers Media S.A. 2018-11-30 /pmc/articles/PMC6283890/ /pubmed/30555440 http://dx.doi.org/10.3389/fmicb.2018.02895 Text en Copyright © 2018 Xu, Zhou, Wu, Zhou, Li, Zhang, Wu, Karakousis and Yao. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Xu, Zhihong
Zhou, Aiping
Wu, Jiawei
Zhou, Aiwu
Li, Jun
Zhang, Shulin
Wu, Wenjuan
Karakousis, Petros C.
Yao, Yu-Feng
Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title_full Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title_fullStr Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title_full_unstemmed Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title_short Transcriptional Approach for Decoding the Mechanism of rpoC Compensatory Mutations for the Fitness Cost in Rifampicin-Resistant Mycobacterium tuberculosis
title_sort transcriptional approach for decoding the mechanism of rpoc compensatory mutations for the fitness cost in rifampicin-resistant mycobacterium tuberculosis
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283890/
https://www.ncbi.nlm.nih.gov/pubmed/30555440
http://dx.doi.org/10.3389/fmicb.2018.02895
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