Perron Gabriel G, Gonzalez Andrew, Buckling Angus
Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK.
Proc Biol Sci. 2007 Sep 22;274(1623):2351-6. doi: 10.1098/rspb.2007.0640.
Understanding the conditions that favour the evolution and maintenance of antibiotic resistance is the central goal of epidemiology. A crucial feature explaining the adaptation to harsh, or 'sink', environments is the supply of beneficial mutations via migration from a 'source' population. Given that antibiotic resistance is frequently associated with antagonistic pleiotropic fitness costs, increased migration rate is predicted not only to increase the rate of resistance evolution but also to increase the probability of fixation of resistance mutations with minimal fitness costs. Here we report in vitro experiments using the nosocomial pathogenic bacterium Pseudomonas aeruginosa that support these predictions: increasing rate of migration into environments containing antibiotics increased the rate of resistance evolution and decreased the associated costs of resistance. Consistent with previous theoretical work, we found that resistance evolution arose more rapidly in the presence of a single antibiotic than two. Evolution of resistance was also more rapid when bacteria were subjected to sequential exposure with two antibiotics (cycling therapy) compared with simultaneous exposure (bi-therapy). Furthermore, pleiotropic fitness costs of resistance to two antibiotics were higher than for one antibiotic, and were also higher under bi-therapy than cycling therapy, although the cost of resistance depended on the order of the antibiotics through time. These results may be relevant to the clinical setting where immigration is known to be important between chemotherapeutically treated patients, and demonstrate the importance of ecological and evolutionary dynamics in the control of antibiotic resistance.
了解有利于抗生素耐药性进化和维持的条件是流行病学的核心目标。解释对恶劣或 “汇” 环境适应的一个关键特征是通过从 “源” 种群迁移来提供有益突变。鉴于抗生素耐药性通常与拮抗性多效性适合度代价相关，预计迁移率的增加不仅会提高耐药性进化的速率，还会增加以最小适合度代价固定耐药性突变的概率。在此，我们报告了使用医院病原菌铜绿假单胞菌进行的体外实验，这些实验支持了这些预测：增加迁移到含抗生素环境中的速率会提高耐药性进化的速率，并降低相关的耐药性代价。与之前的理论研究一致，我们发现，在单一抗生素存在的情况下，耐药性进化比在两种抗生素存在时更快。与同时暴露（双联疗法）相比，当细菌接受两种抗生素的序贯暴露（循环疗法）时，耐药性进化也更快。此外，对两种抗生素耐药的多效性适合度代价高于对一种抗生素耐药的情况，并且在双联疗法下也高于循环疗法，尽管耐药性代价取决于抗生素随时间的顺序。这些结果可能与临床环境相关，在临床环境中，已知化疗患者之间的迁移很重要，并且证明了生态和进化动力学在控制抗生素耐药性方面的重要性。
