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Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates
The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aur...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414891/ https://www.ncbi.nlm.nih.gov/pubmed/32769975 http://dx.doi.org/10.1038/s41467-020-17735-y |
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author | Papkou, Andrei Hedge, Jessica Kapel, Natalia Young, Bernadette MacLean, R. Craig |
author_facet | Papkou, Andrei Hedge, Jessica Kapel, Natalia Young, Bernadette MacLean, R. Craig |
author_sort | Papkou, Andrei |
collection | PubMed |
description | The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome. |
format | Online Article Text |
id | pubmed-7414891 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74148912020-08-17 Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates Papkou, Andrei Hedge, Jessica Kapel, Natalia Young, Bernadette MacLean, R. Craig Nat Commun Article The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome. Nature Publishing Group UK 2020-08-07 /pmc/articles/PMC7414891/ /pubmed/32769975 http://dx.doi.org/10.1038/s41467-020-17735-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Papkou, Andrei Hedge, Jessica Kapel, Natalia Young, Bernadette MacLean, R. Craig Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title | Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title_full | Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title_fullStr | Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title_full_unstemmed | Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title_short | Efflux pump activity potentiates the evolution of antibiotic resistance across S. aureus isolates |
title_sort | efflux pump activity potentiates the evolution of antibiotic resistance across s. aureus isolates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414891/ https://www.ncbi.nlm.nih.gov/pubmed/32769975 http://dx.doi.org/10.1038/s41467-020-17735-y |
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