Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>

ABSTRACT While much attention has been focused on acquired antibiotic resistance genes, chromosomal mutations may be most important in chronic infections where isolated, persistently infecting lineages experience repeated antibiotic exposure. Here, we used experimental evolution and whole-genome seq...

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Autores principales:	Peter Jorth, Kathryn McLean, Anina Ratjen, Patrick R. Secor, Gilbert E. Bautista, Sumedha Ravishankar, Amir Rezayat, Jayanthi Garudathri, Joe J. Harrison, Rachel A. Harwood, Kelsi Penewit, Adam Waalkes, Pradeep K. Singh, Stephen J. Salipante
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Pseudomonas aeruginosa antibiotic resistance aztreonam cystic fibrosis fitness selection Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/3789d0f4355743ab928140bb13ba807a
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spelling	oai:doaj.org-article:3789d0f4355743ab928140bb13ba807a2021-11-15T15:51:51ZEvolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>10.1128/mBio.00517-172150-7511https://doaj.org/article/3789d0f4355743ab928140bb13ba807a2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00517-17https://doaj.org/toc/2150-7511ABSTRACT While much attention has been focused on acquired antibiotic resistance genes, chromosomal mutations may be most important in chronic infections where isolated, persistently infecting lineages experience repeated antibiotic exposure. Here, we used experimental evolution and whole-genome sequencing to investigate chromosomally encoded mutations causing aztreonam resistance in Pseudomonas aeruginosa and characterized the secondary consequences of resistance development. We identified 19 recurrently mutated genes associated with aztreonam resistance. The most frequently observed mutations affected negative transcriptional regulators of the mexAB-oprM efflux system and the target of aztreonam, ftsI. While individual mutations conferred modest resistance gains, high-level resistance (1,024 µg/ml) was achieved through the accumulation of multiple variants. Despite being largely stable when strains were passaged in the absence of antibiotics, aztreonam resistance was associated with decreased in vitro growth rates, indicating an associated fitness cost. In some instances, evolved aztreonam-resistant strains exhibited increased resistance to structurally unrelated antipseudomonal antibiotics. Surprisingly, strains carrying evolved mutations which affected negative regulators of mexAB-oprM (mexR and nalD) demonstrated enhanced virulence in a murine pneumonia infection model. Mutations in these genes, and other genes that we associated with aztreonam resistance, were common in P. aeruginosa isolates from chronically infected patients with cystic fibrosis. These findings illuminate mechanisms of P. aeruginosa aztreonam resistance and raise the possibility that antibiotic treatment could inadvertently select for hypervirulence phenotypes. IMPORTANCE Inhaled aztreonam is a relatively new antibiotic which is being increasingly used to treat cystic fibrosis patients with Pseudomonas aeruginosa airway infections. As for all antimicrobial agents, bacteria can evolve resistance that decreases the effectiveness of the drug; however, the mechanisms and consequences of aztreonam resistance are incompletely understood. Here, using experimental evolution, we have cataloged spontaneous mutations conferring aztreonam resistance and have explored their effects. We found that a diverse collection of genes contributes to aztreonam resistance, each with a small but cumulative effect. Surprisingly, we found that selection for aztreonam resistance mutations could confer increased resistance to other antibiotics and promote hypervirulence in a mouse infection model. Our study reveals inherent mechanisms of aztreonam resistance and indicates that aztreonam exposure can have unintended secondary effects.Peter JorthKathryn McLeanAnina RatjenPatrick R. SecorGilbert E. BautistaSumedha RavishankarAmir RezayatJayanthi GarudathriJoe J. HarrisonRachel A. HarwoodKelsi PenewitAdam WaalkesPradeep K. SinghStephen J. SalipanteAmerican Society for MicrobiologyarticlePseudomonas aeruginosaantibiotic resistanceaztreonamcystic fibrosisfitnessselectionMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pseudomonas aeruginosa antibiotic resistance aztreonam cystic fibrosis fitness selection Microbiology QR1-502
spellingShingle	Pseudomonas aeruginosa antibiotic resistance aztreonam cystic fibrosis fitness selection Microbiology QR1-502 Peter Jorth Kathryn McLean Anina Ratjen Patrick R. Secor Gilbert E. Bautista Sumedha Ravishankar Amir Rezayat Jayanthi Garudathri Joe J. Harrison Rachel A. Harwood Kelsi Penewit Adam Waalkes Pradeep K. Singh Stephen J. Salipante Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
description	ABSTRACT While much attention has been focused on acquired antibiotic resistance genes, chromosomal mutations may be most important in chronic infections where isolated, persistently infecting lineages experience repeated antibiotic exposure. Here, we used experimental evolution and whole-genome sequencing to investigate chromosomally encoded mutations causing aztreonam resistance in Pseudomonas aeruginosa and characterized the secondary consequences of resistance development. We identified 19 recurrently mutated genes associated with aztreonam resistance. The most frequently observed mutations affected negative transcriptional regulators of the mexAB-oprM efflux system and the target of aztreonam, ftsI. While individual mutations conferred modest resistance gains, high-level resistance (1,024 µg/ml) was achieved through the accumulation of multiple variants. Despite being largely stable when strains were passaged in the absence of antibiotics, aztreonam resistance was associated with decreased in vitro growth rates, indicating an associated fitness cost. In some instances, evolved aztreonam-resistant strains exhibited increased resistance to structurally unrelated antipseudomonal antibiotics. Surprisingly, strains carrying evolved mutations which affected negative regulators of mexAB-oprM (mexR and nalD) demonstrated enhanced virulence in a murine pneumonia infection model. Mutations in these genes, and other genes that we associated with aztreonam resistance, were common in P. aeruginosa isolates from chronically infected patients with cystic fibrosis. These findings illuminate mechanisms of P. aeruginosa aztreonam resistance and raise the possibility that antibiotic treatment could inadvertently select for hypervirulence phenotypes. IMPORTANCE Inhaled aztreonam is a relatively new antibiotic which is being increasingly used to treat cystic fibrosis patients with Pseudomonas aeruginosa airway infections. As for all antimicrobial agents, bacteria can evolve resistance that decreases the effectiveness of the drug; however, the mechanisms and consequences of aztreonam resistance are incompletely understood. Here, using experimental evolution, we have cataloged spontaneous mutations conferring aztreonam resistance and have explored their effects. We found that a diverse collection of genes contributes to aztreonam resistance, each with a small but cumulative effect. Surprisingly, we found that selection for aztreonam resistance mutations could confer increased resistance to other antibiotics and promote hypervirulence in a mouse infection model. Our study reveals inherent mechanisms of aztreonam resistance and indicates that aztreonam exposure can have unintended secondary effects.
format	article
author	Peter Jorth Kathryn McLean Anina Ratjen Patrick R. Secor Gilbert E. Bautista Sumedha Ravishankar Amir Rezayat Jayanthi Garudathri Joe J. Harrison Rachel A. Harwood Kelsi Penewit Adam Waalkes Pradeep K. Singh Stephen J. Salipante
author_facet	Peter Jorth Kathryn McLean Anina Ratjen Patrick R. Secor Gilbert E. Bautista Sumedha Ravishankar Amir Rezayat Jayanthi Garudathri Joe J. Harrison Rachel A. Harwood Kelsi Penewit Adam Waalkes Pradeep K. Singh Stephen J. Salipante
author_sort	Peter Jorth
title	Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
title_short	Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
title_full	Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
title_fullStr	Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
title_full_unstemmed	Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>
title_sort	evolved aztreonam resistance is multifactorial and can produce hypervirulence in <italic toggle="yes">pseudomonas aeruginosa</italic>
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/3789d0f4355743ab928140bb13ba807a
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Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in <italic toggle="yes">Pseudomonas aeruginosa</italic>

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