Department of Zoology, University of Oxford, United Kingdom.
Evolution. 2013 Oct;67(10):2973-81. doi: 10.1111/evo.12158. Epub 2013 Jun 5.
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.
抗生素耐药性突变伴随着适应性成本，当抗生素的使用停止后，细菌有两种机制可以适应这种成本。首先，耐药性有可能恢复；其次，细菌可以通过补偿性突变来适应耐药性的成本。不幸的是，抗生素敏感性的恢复是罕见的，但阻止恢复的潜在因素仍不清楚。在这里，我们通过在 Rifampicin 耐药性铜绿假单胞菌的种群中模拟耐药性恢复突变来直接研究恢复的进化动态。我们表明，在我们的种群中，当敏感型很少时，由于遗传漂变，大多数敏感型会丢失。然而，携带补偿性突变的谱系的克隆干扰导致逃避遗传漂变的敏感型固定时间显著增加，并且能够超越敏感型适应性的突变体有能力使暂时常见的敏感谱系灭绝。至关重要的是，我们表明，克隆干扰对恢复的限制取决于耐药种群的补偿适应潜力。尽管耐药性的成本为恢复提供了动力，但我们的研究表明，耐药种群的成本和内在可进化性相互作用，决定了恢复的速度和可能性。
