Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance

ABSTRACT Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibioti...

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Autores principales:	Mark A. Webber, Vito Ricci, Rebekah Whitehead, Meha Patel, Maria Fookes, Alasdair Ivens, Laura J. V. Piddock
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/20f8f0513fc845988a716df0e32a9e8f
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spelling	oai:doaj.org-article:20f8f0513fc845988a716df0e32a9e8f2021-11-15T15:43:09ZClinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance10.1128/mBio.00273-132150-7511https://doaj.org/article/20f8f0513fc845988a716df0e32a9e8f2013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00273-13https://doaj.org/toc/2150-7511ABSTRACT Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. IMPORTANCE Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions.Mark A. WebberVito RicciRebekah WhiteheadMeha PatelMaria FookesAlasdair IvensLaura J. V. PiddockAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Mark A. Webber Vito Ricci Rebekah Whitehead Meha Patel Maria Fookes Alasdair Ivens Laura J. V. Piddock Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
description	ABSTRACT Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. IMPORTANCE Fluoroquinolones are a powerful group of antibiotics that target bacterial enzymes involved in helping bacteria maintain the conformation of their chromosome. Mutations in the target enzymes allow bacteria to become resistant to these antibiotics, and fluoroquinolone resistance is common. We show here that these mutations also provide protection against a broad range of other antimicrobials by triggering a defensive stress response in the cell. This work suggests that fluoroquinolone resistance mutations may be beneficial under a range of conditions.
format	article
author	Mark A. Webber Vito Ricci Rebekah Whitehead Meha Patel Maria Fookes Alasdair Ivens Laura J. V. Piddock
author_facet	Mark A. Webber Vito Ricci Rebekah Whitehead Meha Patel Maria Fookes Alasdair Ivens Laura J. V. Piddock
author_sort	Mark A. Webber
title	Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
title_short	Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
title_full	Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
title_fullStr	Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
title_full_unstemmed	Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance
title_sort	clinically relevant mutant dna gyrase alters supercoiling, changes the transcriptome, and confers multidrug resistance
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/20f8f0513fc845988a716df0e32a9e8f
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Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance

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