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Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa

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 t...

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Autores principales: Jorth, Peter, McLean, Kathryn, Ratjen, Anina, Secor, Patrick R., Bautista, Gilbert E., Ravishankar, Sumedha, Rezayat, Amir, Garudathri, Jayanthi, Harrison, Joe J., Harwood, Rachel A., Penewit, Kelsi, Waalkes, Adam, Singh, Pradeep K., Salipante, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666152/
https://www.ncbi.nlm.nih.gov/pubmed/29089424
http://dx.doi.org/10.1128/mBio.00517-17
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author Jorth, Peter
McLean, Kathryn
Ratjen, Anina
Secor, Patrick R.
Bautista, Gilbert E.
Ravishankar, Sumedha
Rezayat, Amir
Garudathri, Jayanthi
Harrison, Joe J.
Harwood, Rachel A.
Penewit, Kelsi
Waalkes, Adam
Singh, Pradeep K.
Salipante, Stephen J.
author_facet Jorth, Peter
McLean, Kathryn
Ratjen, Anina
Secor, Patrick R.
Bautista, Gilbert E.
Ravishankar, Sumedha
Rezayat, Amir
Garudathri, Jayanthi
Harrison, Joe J.
Harwood, Rachel A.
Penewit, Kelsi
Waalkes, Adam
Singh, Pradeep K.
Salipante, Stephen J.
author_sort Jorth, Peter
collection PubMed
description 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.
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spelling pubmed-56661522017-11-03 Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa Jorth, Peter McLean, Kathryn Ratjen, Anina Secor, Patrick R. Bautista, Gilbert E. Ravishankar, Sumedha Rezayat, Amir Garudathri, Jayanthi Harrison, Joe J. Harwood, Rachel A. Penewit, Kelsi Waalkes, Adam Singh, Pradeep K. Salipante, Stephen J. mBio Research Article 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. American Society for Microbiology 2017-10-31 /pmc/articles/PMC5666152/ /pubmed/29089424 http://dx.doi.org/10.1128/mBio.00517-17 Text en Copyright © 2017 Jorth et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Jorth, Peter
McLean, Kathryn
Ratjen, Anina
Secor, Patrick R.
Bautista, Gilbert E.
Ravishankar, Sumedha
Rezayat, Amir
Garudathri, Jayanthi
Harrison, Joe J.
Harwood, Rachel A.
Penewit, Kelsi
Waalkes, Adam
Singh, Pradeep K.
Salipante, Stephen J.
Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title_full Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title_fullStr Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title_full_unstemmed Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title_short Evolved Aztreonam Resistance Is Multifactorial and Can Produce Hypervirulence in Pseudomonas aeruginosa
title_sort evolved aztreonam resistance is multifactorial and can produce hypervirulence in pseudomonas aeruginosa
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666152/
https://www.ncbi.nlm.nih.gov/pubmed/29089424
http://dx.doi.org/10.1128/mBio.00517-17
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