Evolving Antibiotics against Resistance: a Potential Platform for Natural Product Development?
Evolving Antibiotics against Resistance: a Potential Platform for Natural Product Development?
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DOI：
10.1128/mbio.02946-19
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发表时间：
2019-11-01
期刊：
影响因子：
6.4
通讯作者：
Brown, Sam P.
中科院分区：
文献类型：
--
作者：
Waldetoft, Kristofer Wollein;Gurney, James;Brown, Sam P.
为了避免抗生素耐药性危机，我们需要以与耐药性进化速度相匹配的速度开发抗生素。然而，目前的药物开发方法（包括基于靶点的筛选和合理设计）已经证明，抗生素所具有的复杂功能——结合，例如渗透膜、抵抗耐药机制以及与分子靶点的相互作用——很难实现。在这里，我们认为我们可以在实验室里用抗生素的进化来满足临床的耐药性进化。根据微生物的实验进化研究结果，特别是放线菌的抗生素生产，我们提出了进化抗生素的方法，以绕过耐药机制。这利用了进化的能力，在不需要设计的情况下找到复杂问题的解决方案。我们回顾了对这种方法至关重要的进化理论，并认为它是可行的，并且比目前的抗生素发现方法具有重要的优势。
To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. However, the complex functions performed by antibiotics-combining, e.g., penetration of membranes, counteraction of resistance mechanisms, and interaction with molecular targets-have proven hard to achieve with current methods for drug development, including target-based screening and rational design. Here, we argue that we can meet the evolution of resistance in the clinic with evolution of antibiotics in the laboratory. On the basis of the results of experimental evolution studies of microbes in general and antibiotic production in Actinobacteria in particular, we propose methodology for evolving antibiotics to circumvent mechanisms of resistance. This exploits the ability of evolution to find solutions to complex problems without a need for design. We review evolutionary theory critical to this approach and argue that it is feasible and has important advantages over current methods for antibiotic discovery.