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Mutators can drive ...
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Gifford, Danna R.Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.;Univ Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Earth & Environm Sci, Manchester, England.
(author)
Mutators can drive the evolution of multi-resistance to antibiotics
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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Public Library of Science (PLoS),2023
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printrdacarrier
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LIBRIS-ID:oai:DiVA.org:kth-330645
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-330645URI
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https://doi.org/10.1371/journal.pgen.1010791DOI
Supplementary language notes
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20230630
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Antibiotic combination therapies are an approach used to counter the evolution of resistance; their purported benefit is they can stop the successive emergence of independent resistance mutations in the same genome. Here, we show that bacterial populations with ‘mutators’, organisms with defects in DNA repair, readily evolve resistance to combination antibiotic treatment when there is a delay in reaching inhibitory concentrations of antibiotic—under conditions where purely wild-type populations cannot. In populations of Escherichia coli subjected to combination treatment, we detected a diverse array of acquired mutations, including multiple alleles in the canonical targets of resistance for the two drugs, as well as mutations in multi-drug efflux pumps and genes involved in DNA replication and repair. Unexpectedly, mutators not only allowed multi-resistance to evolve under combination treatment where it was favoured, but also under single-drug treatments. Using simulations, we show that the increase in mutation rate of the two canonical resistance targets is sufficient to permit multi-resistance evolution in both single-drug and combination treatments. Under both conditions, the mutator allele swept to fixation through hitch-hiking with single-drug resistance, enabling subsequent resistance mutations to emerge. Ultimately, our results suggest that mutators may hinder the utility of combination therapy when mutators are present. Additionally, by raising the rates of genetic mutation, selection for multi-resistance may have the unwanted side-effect of increasing the potential to evolve resistance to future antibiotic treatments.
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Berrios-Caro, ErnestoUniv Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Phys & Astron, Manchester, England.;Max Planck Inst Evolutionary Biol, Dept Evolutionary Theory, Plon, Germany.;Christian Albrechts Univ Kiel, Dept Evolutionary Ecol & Genet, Kiel, Germany.
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Joerres, ChristineUniv Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.;Barts Hlth NHS Trust, Royal Hosp, London, England.
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Suñé, MarcUniv Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.;Nordita SU
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Forsyth, Jessica H.Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.
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Bhattacharyya, AnishUniv Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.
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Galla, TobiasUniv Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Phys & Astron, Manchester, England.;CSIC UIB, Inst Fis Interdisciplinar & Sistemas Complejos, Palma De Mallorca, Spain.
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Knight, Christopher G.Univ Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Earth & Environm Sci, Manchester, England.
(author)
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Univ Manchester, Fac Biol Med & Hlth, Sch Biol Sci, Div Evolut Infect & Genom, Manchester, England.;Univ Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Earth & Environm Sci, Manchester, England.Univ Manchester, Fac Sci & Engn, Sch Nat Sci, Dept Phys & Astron, Manchester, England.;Max Planck Inst Evolutionary Biol, Dept Evolutionary Theory, Plon, Germany.;Christian Albrechts Univ Kiel, Dept Evolutionary Ecol & Genet, Kiel, Germany.
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In:PLOS Genetics: Public Library of Science (PLoS)19:61553-73901553-7404
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