Metabolic Control of Persister Formation in Escherichia coli
Metabolic Control of Persister Formation in Escherichia coli
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DOI：
10.1016/j.molcel.2013.04.002
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发表时间：
2013-05-23
期刊：
影响因子：
16
通讯作者：
Brynildsen, Mark P.
中科院分区：
文献类型：
--
作者：
Amato, Stephanie M.;Orman, Mehmet A.;Brynildsen, Mark P.
细菌持留菌是由应激反应途径的作用形成的表型变体，其触发毒素介导的抗生素耐受性。虽然持续形成在正常的生长过程中从自然应力，负责这种现象的途径仍然难以捉摸。在这里，我们已经发现，碳源转换刺激大肠杆菌中氟喹诺酮类药物持久性的形成。此外，通过结合遗传，生化和流式细胞术分析与数学模型，我们已经重建了分子水平的持久性形成途径，从初始压力（葡萄糖耗尽）激活的代谢毒素-抗毒素（TA）模块（ppGpp生化网络），导致抑制DNA促旋酶活性，氟喹诺酮类药物的主要目标。该途径从初始应激跨越到抗生素靶标，并证明TA行为可以通过代谢物-酶相互作用（ppGpp-SpoT）来表现，这与仅涉及蛋白质和/或RNA的经典TA系统相反。
Bacterial persisters are phenotypic variants that form from the action of stress response pathways triggering toxin-mediated antibiotic tolerance. Although persisters form during normal growth from native stresses, the pathways responsible for this phenomenon remain elusive. Here we have discovered that carbon source transitions stimulate the formation of fluoroquinolone persisters in Escherichia coli. Further, through a combination of genetic, biochemical, and flow cytometric assays in conjunction with a mathematical model, we have reconstructed a molecular-level persister formation pathway from initial stress (glucose exhaustion) to the activation of a metabolic toxin-antitoxin (TA) module (the ppGpp biochemical network) resulting in inhibition of DNA gyrase activity, the primary target of fluoroquinolones. This pathway spans from initial stress to antibiotic target and demonstrates that TA behavior can be exhibited by a metabolite-enzyme interaction (ppGpp-SpoT), in contrast to classical TA systems that involve only protein and/or RNA.