Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

ABSTRACT Fitness costs play a key role in the evolutionary dynamics of antibiotic resistance in bacteria by generating selection against resistance in the absence of antibiotics. Although the genetic basis of antibiotic resistance is well understood, the precise molecular mechanisms linking the gene...

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Autores principales:	Qin Qi, Gail M. Preston, R. Craig MacLean
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d6f8f69b1fba4c6a8098ccf75de983fa
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spelling	oai:doaj.org-article:d6f8f69b1fba4c6a8098ccf75de983fa2021-11-15T15:47:04ZLinking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>10.1128/mBio.01562-142150-7511https://doaj.org/article/d6f8f69b1fba4c6a8098ccf75de983fa2014-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01562-14https://doaj.org/toc/2150-7511ABSTRACT Fitness costs play a key role in the evolutionary dynamics of antibiotic resistance in bacteria by generating selection against resistance in the absence of antibiotics. Although the genetic basis of antibiotic resistance is well understood, the precise molecular mechanisms linking the genetic basis of resistance to its fitness cost remain poorly characterized. Here, we examine how the system-wide impacts of mutations in the RNA polymerase (RNAP) gene rpoB shape the fitness cost of rifampin resistance in Pseudomonas aeruginosa. Rifampin resistance mutations reduce transcriptional efficiency, and this explains 76% of the variation in fitness among rpoB mutants. The pleiotropic consequence of rpoB mutations is that mutants show altered relative transcript levels of essential genes. We find no evidence that global transcriptional responses have an impact on the fitness cost of rifampin resistance as revealed by transcriptome sequencing (RNA-Seq). Global changes in the transcriptional profiles of rpoB mutants compared to the transcriptional profile of the rifampin-sensitive ancestral strain are subtle, demonstrating that the transcriptional regulatory network of P. aeruginosa is robust to the decreased transcriptional efficiency associated with rpoB mutations. On a smaller scale, we find that rifampin resistance mutations increase the expression of RNAP due to decreased termination at an attenuator upstream from rpoB, and we argue that this helps to minimize the cost of rifampin resistance by buffering against reduced RNAP activity. In summary, our study shows that it is possible to dissect the molecular mechanisms underpinning variation in the cost of rifampin resistance and highlights the importance of genome-wide buffering of relative transcript levels in providing robustness against resistance mutations. IMPORTANCE Antibiotic resistance mutations carry fitness costs. Relative to the characteristics of their antibiotic-sensitive ancestors, resistant mutants show reduced growth rates and competitive abilities. Fitness cost plays an important role in the evolution of antibiotic resistance in the absence of antibiotics; however, the molecular mechanisms underlying these fitness costs is not well understood. We applied a systems-level approach to dissect the molecular underpinnings of the fitness costs associated with rifampin resistance in P. aeruginosa and showed that most of the variation in fitness cost can be explained by the direct effect of resistance mutations on the enzymatic activity of the mutated gene. Pleiotropic changes in transcriptional profiles are subtle at a genome-wide scale, suggesting that the gene regulatory network of P. aeruginosa is robust in the face of the direct effects of resistance mutations.Qin QiGail M. PrestonR. Craig MacLeanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 6 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Qin Qi Gail M. Preston R. Craig MacLean Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
description	ABSTRACT Fitness costs play a key role in the evolutionary dynamics of antibiotic resistance in bacteria by generating selection against resistance in the absence of antibiotics. Although the genetic basis of antibiotic resistance is well understood, the precise molecular mechanisms linking the genetic basis of resistance to its fitness cost remain poorly characterized. Here, we examine how the system-wide impacts of mutations in the RNA polymerase (RNAP) gene rpoB shape the fitness cost of rifampin resistance in Pseudomonas aeruginosa. Rifampin resistance mutations reduce transcriptional efficiency, and this explains 76% of the variation in fitness among rpoB mutants. The pleiotropic consequence of rpoB mutations is that mutants show altered relative transcript levels of essential genes. We find no evidence that global transcriptional responses have an impact on the fitness cost of rifampin resistance as revealed by transcriptome sequencing (RNA-Seq). Global changes in the transcriptional profiles of rpoB mutants compared to the transcriptional profile of the rifampin-sensitive ancestral strain are subtle, demonstrating that the transcriptional regulatory network of P. aeruginosa is robust to the decreased transcriptional efficiency associated with rpoB mutations. On a smaller scale, we find that rifampin resistance mutations increase the expression of RNAP due to decreased termination at an attenuator upstream from rpoB, and we argue that this helps to minimize the cost of rifampin resistance by buffering against reduced RNAP activity. In summary, our study shows that it is possible to dissect the molecular mechanisms underpinning variation in the cost of rifampin resistance and highlights the importance of genome-wide buffering of relative transcript levels in providing robustness against resistance mutations. IMPORTANCE Antibiotic resistance mutations carry fitness costs. Relative to the characteristics of their antibiotic-sensitive ancestors, resistant mutants show reduced growth rates and competitive abilities. Fitness cost plays an important role in the evolution of antibiotic resistance in the absence of antibiotics; however, the molecular mechanisms underlying these fitness costs is not well understood. We applied a systems-level approach to dissect the molecular underpinnings of the fitness costs associated with rifampin resistance in P. aeruginosa and showed that most of the variation in fitness cost can be explained by the direct effect of resistance mutations on the enzymatic activity of the mutated gene. Pleiotropic changes in transcriptional profiles are subtle at a genome-wide scale, suggesting that the gene regulatory network of P. aeruginosa is robust in the face of the direct effects of resistance mutations.
format	article
author	Qin Qi Gail M. Preston R. Craig MacLean
author_facet	Qin Qi Gail M. Preston R. Craig MacLean
author_sort	Qin Qi
title	Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_short	Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full	Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_fullStr	Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_full_unstemmed	Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>
title_sort	linking system-wide impacts of rna polymerase mutations to the fitness cost of rifampin resistance in <named-content content-type="genus-species">pseudomonas aeruginosa</named-content>
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/d6f8f69b1fba4c6a8098ccf75de983fa
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Linking System-Wide Impacts of RNA Polymerase Mutations to the Fitness Cost of Rifampin Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>

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