Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance
Alternating antibiotic treatments constrain evolutionary paths to multidrug resistance
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DOI：
10.1073/pnas.1409800111
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发表时间：
2014-10-07
影响因子：
11.1
通讯作者：
Kishony, Roy
中科院分区：
文献类型：
--
作者：
Kim, Seungsoo;Lieberman, Tami D.;Kishony, Roy
交替抗生素疗法（即在治疗期间循环使用成对药物）已被建议作为抑制从头耐药性演变的一种手段，同时避免与更传统的联合疗法相关的毒性。然而，目前尚不清楚这种交替治疗在什么条件下以及通过什么方式阻碍耐药性的进化。在这里，我们追踪了金黄色葡萄球菌复制群体在 22 天内不断增加的单一、混合和交替药物治疗期间耐药性的多步进化。在所有三个测试的药物对中，交替治疗通过减缓对两种成分药物之一的耐药性的获得来降低总体耐药率，有时与混合治疗一样有效。这种较慢的进化速度反映在全基因组突变谱中；在交替治疗下，细菌在不同的基因中获得突变，而不是在相应的单一药物治疗下。为了测试这种观察到的对适应性路径的限制是否反映了对一种药物的耐药性伴随着对另一种药物的敏感性的权衡，我们分析了许多单步突变体的交叉耐药性。事实上，单步突变体的平均交叉耐药性可以帮助预测交替药物的进化是否较慢。总之，这些结果表明，尽管多药耐药性的进化景观很复杂，但交替药物治疗可以通过限制耐药性的突变路径来减缓进化。
Alternating antibiotic therapy, in which pairs of drugs are cycled during treatment, has been suggested as a means to inhibit the evolution of de novo resistance while avoiding the toxicity associated with more traditional combination therapy. However, it remains unclear under which conditions and by what means such alternating treatments impede the evolution of resistance. Here, we tracked multistep evolution of resistance in replicate populations of Staphylococcus aureus during 22 d of continuously increasing single-, mixed-, and alternating-drug treatment. In all three tested drug pairs, the alternating treatment reduced the overall rate of resistance by slowing the acquisition of resistance to one of the two component drugs, sometimes as effectively as mixed treatment. This slower rate of evolution is reflected in the genome-wide mutational profiles; under alternating treatments, bacteria acquire mutations in different genes than under corresponding single-drug treatments. To test whether this observed constraint on adaptive paths reflects trade-offs in which resistance to one drug is accompanied by sensitivity to a second drug, we profiled many single-step mutants for cross-resistance. Indeed, the average cross-resistance of single-step mutants can help predict whether or not evolution was slower in alternating drugs. Together, these results show that despite the complex evolutionary landscape of multidrug resistance, alternating-drug therapy can slow evolution by constraining the mutational paths toward resistance.