通过确定和理解当地适应性景观来设计抗生素循环策略
Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes
摘要：
细菌抗生素耐药性的演变威胁着我们治疗传染病的持续能力。对治疗细菌感染的可持续战略的需求从未如此强烈。到目前为止，所有在耐药性出现后恢复敏感性的尝试都没有成功，包括限制处方[1]和抗生素循环[2，3]。部分问题可能是这些努力已经实施了不同类别的不相关抗生素，并依赖于通过细菌种群中抗性基因的随机丢失（漂移）来消除抗性。在这里，我们表明，交替使用结构相似的抗生素可以在耐药性形成后恢复对抗生素的敏感性。我们发现，编码TEM β-内酰胺酶的耐药基因（blaTEM）的变异等位基因所赋予的耐药表型在15种不同的β-内酰胺类抗生素中差异很大。我们通过表征抗性等位基因blaTEM-50和blaTEM-85的完整适应性景观来捕获这些差异，每个等位基因与其祖先blaTEM-1都有四个突变。我们通过这些景观确定了途径，其中随着抗生素的交替，增加抗性的选择在有限的等位基因组中重复循环。我们的研究结果表明，对抗生素的敏感性可以通过循环结构相似的抗生素来持续更新。我们预计，这些结果可能为管理抗生素耐药性提供一个概念框架。这种方法还可以指导用于治疗疟疾和艾滋病毒的药物的可持续循环。
英文摘要：
The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2,3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM β-lactamase (blaTEM) varied greatly among 15 different β-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles blaTEM-50 and blaTEM-85, each of which differs from its ancestor blaTEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV.
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