Wright, Rosanna Christina Taylor, Friman, Ville-Petri orcid.org/0000-0002-1592-157X, Smith, Margaret Caroline MacHin orcid.org/0000-0002-4150-0496 et al. (1 more author) (2019) Resistance evolution against phage combinations depends on the timing and order of exposure. MBio. e01652-19. ISSN 2150-7511
Abstract
Phage therapy is a promising alternative to chemotherapeutic antibiotics for the treatment of bacterial infections. However, despite recent clinical uses of combinations of phages to treat multidrug resistant infections, a mechanistic understanding of how bacteria evolve resistance against multiple phages is lacking, limiting our ability to deploy phage combinations optimally. Here we show, using Pseudomonas aeruginosa and pairs of phages targeting shared or distinct surface receptors, that the timing and order of phage exposure determines the strength, cost and mutational basis of resistance. Whereas sequential exposure allowed bacteria to acquire multiple resistance mutations effective against both phages, this evolutionary trajectory was prevented by simultaneous exposure, resulting in quantitatively weaker resistance. The order of phage exposure determined the fitness costs of sequential resistance, such that certain sequential orders imposed much higher fitness costs than the same phage pair in the reverse order. Together these data suggest that phage combinations can be optimised to limit the strength of evolved resistances whilst maximising their associated fitness costs to promote the long-term efficacy of phage therapy.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 Wright et al. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 30 Aug 2019 08:40 |
Last Modified: | 07 Dec 2024 00:17 |
Published Version: | https://doi.org/10.1128/mBio.01652-19 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1128/mBio.01652-19 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:150225 |
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