Mutators drive evolution of multi-resistance to antibiotics

作者：Danna R. Gifford, Ernesto Berríos-Caro, Christine Joerres, Marc Suñé, Jessica Forsyth, Anish Bhattacharyya, Tobias Galla, Christopher G. Knight · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2019 · DOI：10.1101/643585 · 被引用次数：8 · 研究领域：Evolution and Genetic Dynamics、Antibiotic Resistance in Bacteria、Antibiotics Pharmacokinetics and Efficacy

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 subjected to combination treatment, we detected a remarkable amount of genomic diversity in resistance-determining mutations, multi-drug efflux pumps, and mutation-rate altering genes. However, using eco-evolutionary simulations, we demonstrate that only the initial mutator allele is required to explain multi-resistance evolution. Unexpectedly, mutators not only allowed multi-resistance to evolve under combination treatment where it was favoured, but also under single-drug 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 population mutation, selection for multi-resistance may have the unwanted side-effect of increasing the potential to evolve resistance to future antibiotic tre...