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.
Highlights
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and remains a major global health problem due to its high burden and death worldwide
Song et al (2014) reported that M. tuberculosis RpoC F452L and V483G alleles restored the transcription efficiency of RNA polymerase bearing RpoB S450L mutation. These findings suggest potential compensatory effects of rpoA or rpoC mutations for fitness costs associated with rpoB mutations in M. tuberculosis, the compensatory effect needs to be validated and the underlying molecular mechanisms remain to be elucidated
16 M. tuberculosis clinical isolates were evaluated for inclusion in this study
Summary
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and remains a major global health problem due to its high burden and death worldwide. Mutations in the rpoC gene, encoding the β’ subunit of RNA polymerase, were associated with altered transcript elongation rate and gene expression, leading to metabolic changes and increased growth rate in rifampin-resistant E. coli (Conrad et al, 2010). Song et al (2014) reported that M. tuberculosis RpoC F452L and V483G alleles restored the transcription efficiency of RNA polymerase bearing RpoB S450L mutation. These findings suggest potential compensatory effects of rpoA or rpoC mutations for fitness costs associated with rpoB mutations in M. tuberculosis, the compensatory effect needs to be validated and the underlying molecular mechanisms remain to be elucidated
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