Data from: Evolutionary reversals of antibiotic resistance in experimental populations of Pseudomonas aeruginosa

Antibiotic resistance mutations are accompanied by a fitness cost, and two mechanisms allow bacteria to adapt to this cost once antibiotic use is halted. First, it is possible for resistance to revert; second, it is possible for bacteria to adapt to the cost of resistance by compensatory mutations. Unfortunately, reversion to antibiotic sensitivity is rare, but the underlying factors that prevent reversion remain obscure. Here, we directly study the evolutionary dynamics of reversion by experimentally mimicking reversion mutations—sensitives—in populations of rifampicin-resistant Pseudomonas aeruginosa. We show that, in our populations, most sensitives are lost due to genetic drift when they are rare. However, clonal interference from lineages carrying compensatory mutations causes a dramatic increase in the time to fixation of sensitives that escape genetic drift, and mutations surpassing the sensitives’ fitness are capable of driving transiently common sensitive lineages to extinction. Crucially, we show that the constraints on reversion arising from clonal interference are determined by the potential for compensatory adaptation of the resistant population. Although the cost of resistance provides the incentive for reversion, our study demonstrates that both the cost of resistance and the intrinsic evolvability of resistant populations interact to determine the rate and likelihood of reversion.

抗生素抗性突变往往伴随适应性代价（fitness cost），当抗生素使用停止后，细菌可通过两种机制适应这一代价：其一，抗性可发生回复突变；其二，细菌可通过补偿性突变（compensatory mutations）适应抗性带来的适应性代价。遗憾的是，回复为抗生素敏感型的突变事件极为罕见，但其背后阻碍回复的核心机制仍不明晰。本研究通过在利福平（rifampicin）抗性铜绿假单胞菌（Pseudomonas aeruginosa）种群中人工模拟回复突变——即敏感型菌株的产生——直接探究回复突变的进化动力学过程。研究结果显示，在本实验种群中，多数敏感型菌株在种群频率较低时会因遗传漂变（genetic drift）而丢失。然而，携带补偿性突变的谱系所引发的克隆干涉（clonal interference），会使那些逃过遗传漂变的敏感型菌株的固定时间大幅延长；而适应性优于敏感型菌株的突变株，可将暂时占据一定种群比例的敏感谱系彻底清除。尤为关键的是，本研究表明，克隆干涉所带来的回复突变限制，取决于抗性种群的补偿性适应潜力。尽管抗性代价是驱动回复突变的诱因，但本研究证实，抗性代价与抗性种群的内在进化潜力（evolvability）共同作用，决定了回复突变的发生速率与可能性。