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（antibiotic resistance mutations）往往伴随适合度代价（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：其一为抗性性状发生回复突变；其二为细菌通过补偿突变（compensatory mutations）适配抗性带来的适合度代价。遗憾的是，回复为抗生素敏感型的突变极为罕见，而阻碍回复突变发生的潜在机制仍尚不明确。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），直接探究了回复突变的进化动力学。研究结果显示，在本实验种群中，多数敏感型菌株在其种群频率较低时会因遗传漂变（genetic drift）而丢失。然而，携带补偿突变的谱系所引发的克隆干扰（clonal interference），会显著延长成功逃脱遗传漂变的敏感型菌株的固定时长；而适合度超越敏感型菌株的突变，可将短暂处于高频状态的敏感谱系推向灭绝。至关重要的是，本研究表明，克隆干扰所带来的回复突变限制，取决于抗性种群发生补偿适应性进化的潜力。尽管抗性的适合度代价为回复突变提供了选择动力，但本研究证实，抗性的适合度代价与抗性种群自身的进化潜能共同决定了回复突变的发生速率与可能性。