Department of Zoology, University of Oxford, 11a Mansfield Road, Oxford, OX1 3PS, UK.
Department of Evolutionary Biology and Environmental Studies, University of Zurich, Winterthurerstrasse 190, Zurich, CH-8057, Switzerland.
Nat Commun. 2020 Aug 7;11(1):3970. doi: 10.1038/s41467-020-17735-y.
The rise of antibiotic resistance in many bacterial pathogens has been driven by the spread of a few successful strains, suggesting that some bacteria are genetically pre-disposed to evolving resistance. Here, we test this hypothesis by challenging a diverse set of 222 isolates of Staphylococcus aureus with the antibiotic ciprofloxacin in a large-scale evolution experiment. We find that a single efflux pump, norA, causes widespread variation in evolvability across isolates. Elevated norA expression potentiates evolution by increasing the fitness benefit provided by DNA topoisomerase mutations under ciprofloxacin treatment. Amplification of norA provides a further mechanism of rapid evolution in isolates from the CC398 lineage. Crucially, chemical inhibition of NorA effectively prevents the evolution of resistance in all isolates. Our study shows that pre-existing genetic diversity plays a key role in shaping resistance evolution, and it may be possible to predict which strains are likely to evolve resistance and to optimize inhibitor use to prevent this outcome.
许多细菌病原体对抗生素耐药性的上升是由少数成功菌株的传播所驱动的，这表明某些细菌在遗传上更容易产生耐药性。在这里，我们通过在大规模进化实验中用抗生素环丙沙星挑战 222 株金黄色葡萄球菌的多样性分离株来检验这一假设。我们发现，一种单一的外排泵 norA 导致分离株的可进化性发生广泛变化。norA 表达的升高通过增加 DNA 拓扑异构酶突变在环丙沙星处理下提供的适应性益处，促进了进化。norA 的扩增为 CC398 谱系分离株的快速进化提供了另一种机制。至关重要的是，NorA 的化学抑制有效地阻止了所有分离株的耐药性进化。我们的研究表明，预先存在的遗传多样性在塑造耐药性进化方面起着关键作用，因此有可能预测哪些菌株可能会进化出耐药性，并优化抑制剂的使用以防止这种结果。
