Antibiotic interactions that select against resistance
Antibiotic interactions that select against resistance
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DOI：
10.1038/nature05685
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发表时间：
2007-04-05
期刊：
影响因子：
64.8
通讯作者：
Kishony, Roy
中科院分区：
文献类型：
--
作者：
Chait, Remy;Craney, Allison;Kishony, Roy
多药联用在对抗细菌病原体耐药性传播方面越来越重要（1-3）。在更广泛的范围内，这种组合对于理解微生物生态学和进化也很重要（4，5）。虽然多药联合对细菌生长的影响已被广泛研究，但其对敏感和耐药细菌种群之间的差异选择的影响知之甚少（1，6，7）。通常，药物的存在赋予其抗性突变体与敏感野生型群体竞争的优势（1）。在这里，我们表明，通过使用强力霉素耐药和强力霉素敏感的大肠杆菌之间的直接竞争试验，这种差异选择可以在超拮抗类药物组合中逆转。在这样的组合中使用，药物可以使组合治疗对药物自身的抗性等位基因具有选择性。此外，这种选择的逆转似乎在很大程度上对潜在的抗性机制不敏感，并且在亚致死浓度下发生，同时保持对野生型的抑制。这些看似矛盾的结果可以用一个简单的几何论证来合理化。我们的研究结果表明，以前不受重视的功能的健身景观的演变阻力和点之间的权衡药物相互作用的绝对效力和相对的竞争性选择，他们强加给新兴的耐药群体。
Multidrug combinations are increasingly important in combating the spread of antibiotic-resistance in bacterial pathogens(1-3). On a broader scale, such combinations are also important in understanding microbial ecology and evolution(4,5). Although the effects of multidrug combinations on bacterial growth have been studied extensively, relatively little is known about their impact on the differential selection between sensitive and resistant bacterial populations(1,6,7). Normally, the presence of a drug confers an advantage on its resistant mutants incompetition with the sensitive wild-type population(1). Here we show, by using a direct competition assay between doxycycline-resistant and doxycycline-sensitive Escherichia coli, that this differential selection can be inverted in a hyper-antagonistic class of drug combinations. Used in such a combination, a drug can render the combined treatment selective against the drug's own resistance allele. Further, this inversion of selection seems largely insensitive to the underlying resistance mechanism and occurs, at sublethal concentrations, while maintaining inhibition of the wild type. These seemingly paradoxical results can be rationalized in terms of a simple geometric argument. Our findings demonstrate a previously unappreciated feature of the fitness landscape for the evolution of resistance and point to a trade-off between the effect of drug interactions on absolute potency and the relative competitive selection that they impose on emerging resistant populations.