ArticlePLoS genetics2023
Mutators can drive the evolution of multi-resistance to antibiotics.
Article in PLoS genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 43 citations in OpenAlex.
- Prevalence and mechanisms of antimicrobial resistance in respiratory bacterial pathogens of ruminants: a systematic review.Veterinary research communications · 2025Pooled it
- Article
- Epistasis and co-adaptation in bacterial genome evolution.Nature reviews. Genetics · 2026Review
- Resistance potentiators: Evolutionary catalysts of antibiotic resistance.PLoS biology · 2026Article
- Acinetobacter baumannii encodes multiple mutagenically and biochemically active DNA polymerase V variants.Nucleic acids research · 2026Article
- "Excluded phenotypes" restrict genetic paths toward adaptation in declining populations.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The role of environmental stress in promoting mutators through evolutionary rescue: quantitative predictions.Genetics · 2025Article
- Article
- Antimutator and Mutational Spectrum Effects Can Combine to Reduce Evolutionary Potential in Escherichia coli ΔnudJ.Molecular biology and evolution · 2025Article
- Mutation bias alters the distribution of fitness effects of mutations.PLoS biology · 2025Article
- Genome wide analyses reveal the role of mutator phenotypes in Mycobacterium tuberculosis drug resistance emergence.npj antimicrobials and resistance · 2025Article
- Dual Mutations inInternational journal of molecular sciences · 2025Article
- Evolution of Escherichia coli strains under competent or compromised adaptive immunity.PLoS pathogens · 2025Article
- Quantitative analysis of relationship between mutation rate and speed of adaptation under antibiotic exposure in Escherichia coli.PLoS genetics · 2025Article
- High-throughput method characterizes hundreds of previously unknown antibiotic resistance mutations.Nature communications · 2025Article
- Multiplicity of type 6 secretion system toxins limits the evolution of resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance.Nature communications · 2024Article
- Pathogen-encoded Rum DNA polymerase drives rapid bacterial drug resistance.Nucleic acids research · 2024Article
- From Petri Dishes to Patients to Populations: Scales and Evolutionary Mechanisms Driving Antibiotic Resistance.Annual review of microbiology · 2024Review
- The many dimensions of combination therapy: How to combine antibiotics to limit resistance evolution.Evolutionary applications · 2024Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 3 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.