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首页> 外文期刊>The Journal of Antibiotics: An International Journal >Using experimental evolution to identify druggable targets that could inhibit the evolution of antimicrobial resistance
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Using experimental evolution to identify druggable targets that could inhibit the evolution of antimicrobial resistance

机译：使用实验进化来鉴定可抑制抗菌性抗性演变的可药剂靶标

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With multi-drug and pan-drug-resistant bacteria becoming increasingly common in hospitals, antibiotic resistance has threatened to return us to a pre-antibiotic era that would completely undermine modern medicine. There is an urgent need to develop new antibiotics and strategies to combat resistance that are substantially different from earlier drug discovery efforts. One such strategy that would complement current and future antibiotics would be a class of co-drugs that target the evolution of resistance and thereby extend the efficacy of specific classes of antibiotics. A critical step in the development of such strategies lies in understanding the critical evolutionary trajectories responsible for resistance and which proteins or biochemical pathways within those trajectories would be good candidates for co-drug discovery. We identify the most important steps in the evolution of resistance for a specific pathogen and antibiotic combination by evolving highly polymorphic populations of pathogens to resistance in a novel bioreactor that favors biofilm development. As the populations evolve to increasing drug concentrations, we use deep sequencing to elucidate the network of genetic changes responsible for resistance and subsequent in vitro biochemistry and often structure determination to determine how the adaptive mutations produce resistance. Importantly, the identification of the molecular steps, their frequency within the populations and their chronology within the evolutionary trajectory toward resistance is critical to assessing their relative importance. In this work, we discuss findings from the evolution of the ESKAPE pathogen, Pseudomonas aeruginosa to the drug of last resort, colistin to illustrate the power of this approach.
机译：随着多药耐药和泛耐药细菌在医院中变得越来越普遍，抗生素耐药性已经威胁到我们将回到一个完全破坏现代医学的前抗生素时代。迫切需要开发新的抗生素和策略来对抗耐药性，这与早期的药物研发工作有很大不同。其中一种补充当前和未来抗生素的策略将是一类针对耐药性演变的联合药物，从而延长特定类别抗生素的疗效。开发这类策略的关键一步在于理解导致耐药性的关键进化轨迹，以及这些轨迹中哪些蛋白质或生化途径是很好的联合药物发现候选。我们通过在一种有利于生物膜形成的新型生物反应器中进化高度多态性的病原体群体来识别特定病原体和抗生素组合耐药性进化中最重要的步骤。随着种群进化到药物浓度不断增加，我们使用深度测序来阐明导致耐药性的基因变化网络，以及随后的体外生物化学和结构测定，以确定适应性突变如何产生耐药性。重要的是，确定分子步骤、它们在种群中的频率以及它们在抗性进化轨迹中的时间顺序，对于评估它们的相对重要性至关重要。在这项工作中，我们讨论了从ESKAPE病原体铜绿假单胞菌到最后一种药物粘菌素的演变，以说明这种方法的威力。

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