Effective treatment of bacterial infections proves increasingly challenging due to the emergence of bacterial variants that endure antibiotic exposure. Antibiotic resistance and persistence have been identified as two major bacterial survival mechanisms, and several studies have shown a rapid and strong selection of resistance or persistence mutants under repeated drug treatment. Yet, little is known about the impact of the environmental conditions on resistance and persistence evolution, and the potential interplay between both phenotypes. Based on the distinct growth and survival characteristics of resistance and persistence mutants, we hypothesized that the antibiotic dose and availability of nutrients during treatment might play a key role in the evolutionary adaptation to antibiotic stress. To test this hypothesis, we combined high-throughput experimental evolution with a mathematical model of bacterial evolution under intermittent antibiotic exposure. We show that high nutrient levels during antibiotic treatment promote selection of high-level resistance, but that resistance mainly emerges independently of persistence when the antibiotic concentration is sufficiently low. At higher doses, resistance evolution is facilitated by the preceding or concurrent selection of persistence mutants, which ensures survival of populations in harsh conditions. Collectively, our experimental data and mathematical model elucidate the evolutionary routes towards increased bacterial survival under different antibiotic treatment schedules, which is key to designing effective antibiotic therapies.

中文翻译：

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抗生素剂量和营养可用性不同程度地驱动抗生素耐药性和持久性的演变

由于耐受抗生素暴露的细菌变种的出现，有效治疗细菌感染变得越来越具有挑战性。抗生素耐药性和持久性已被确定为两种主要的细菌生存机制，多项研究表明，在重复药物治疗下，耐药性或持久性突变体会快速而有力地选择。然而，人们对环境条件对抗性和持久性进化的影响以及两种表型之间的潜在相互作用知之甚少。基于抗性和持久性突变体独特的生长和生存特征，我们假设治疗期间的抗生素剂量和营养物质的可用性可能在抗生素应激的进化适应中发挥关键作用。为了检验这一假设，我们将高通量实验进化与间歇性抗生素暴露下细菌进化的数学模型结合起来。我们表明，抗生素治疗期间的高营养水平促进了高水平抗性的选择，但当抗生素浓度足够低时，抗性主要是独立于持久性而出现的。在较高剂量下，持久性突变体的先前或同时选择促进了抗性进化，这确保了种群在恶劣条件下的生存。总的来说，我们的实验数据和数学模型阐明了在不同抗生素治疗方案下提高细菌存活率的进化途径，这是设计有效抗生素疗法的关键。