Mutators can drive the evolution of multi-resistance to antibiotics.
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 d...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010791&type=printable |
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| author | Danna R Gifford Ernesto Berríos-Caro Christine Joerres Marc Suñé Jessica H Forsyth Anish Bhattacharyya Tobias Galla Christopher G Knight |
| author_facet | Danna R Gifford Ernesto Berríos-Caro Christine Joerres Marc Suñé Jessica H Forsyth Anish Bhattacharyya Tobias Galla Christopher G Knight |
| author_sort | Danna R Gifford |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-618e28fcca6d4a6fadc5b96b05db89c2 |
| institution | Kabale University |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2023-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-618e28fcca6d4a6fadc5b96b05db89c22025-08-20T03:46:20ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042023-06-01196e101079110.1371/journal.pgen.1010791Mutators can drive the evolution of multi-resistance to antibiotics.Danna R GiffordErnesto Berríos-CaroChristine JoerresMarc SuñéJessica H ForsythAnish BhattacharyyaTobias GallaChristopher G KnightAntibiotic 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.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010791&type=printable |
| spellingShingle | Danna R Gifford Ernesto Berríos-Caro Christine Joerres Marc Suñé Jessica H Forsyth Anish Bhattacharyya Tobias Galla Christopher G Knight Mutators can drive the evolution of multi-resistance to antibiotics. PLoS Genetics |
| title | Mutators can drive the evolution of multi-resistance to antibiotics. |
| title_full | Mutators can drive the evolution of multi-resistance to antibiotics. |
| title_fullStr | Mutators can drive the evolution of multi-resistance to antibiotics. |
| title_full_unstemmed | Mutators can drive the evolution of multi-resistance to antibiotics. |
| title_short | Mutators can drive the evolution of multi-resistance to antibiotics. |
| title_sort | mutators can drive the evolution of multi resistance to antibiotics |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1010791&type=printable |
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