Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
Department of Physics and Graduate Institute of Biophysics, National Central University, Jhong-Li, Taoyuan 32001, Republic of China.
Mol Cell. 2019 Jan 3;73(1):143-156.e4. doi: 10.1016/j.molcel.2018.10.022. Epub 2018 Nov 21.
Cell dormancy is a widespread mechanism used by bacteria to evade environmental threats, including antibiotics. Here we monitored bacterial antibiotic tolerance and regrowth at the single-cell level and found that each individual survival cell shows different "dormancy depth," which in return regulates the lag time for cell resuscitation after removal of antibiotic. We further established that protein aggresome-a collection of endogenous protein aggregates-is an important indicator of bacterial dormancy depth, whose formation is promoted by decreased cellular ATP level. For cells to leave the dormant state and resuscitate, clearance of protein aggresome and recovery of proteostasis are required. We revealed that the ability to recruit functional DnaK-ClpB machineries, which facilitate protein disaggregation in an ATP-dependent manner, determines the lag time for bacterial regrowth. Better understanding of the key factors regulating bacterial regrowth after surviving antibiotic attack could lead to new therapeutic strategies for combating bacterial antibiotic tolerance.
细胞休眠是细菌用来逃避环境威胁（包括抗生素）的一种广泛机制。在这里，我们在单细胞水平上监测了细菌对抗生素的耐受性和再生长，发现每个存活细胞都表现出不同的“休眠深度”，这反过来又调节了抗生素去除后细胞复苏的滞后时间。我们进一步证实，蛋白聚集体（一种内源性蛋白聚集体的集合）是细菌休眠深度的一个重要指标，其形成是由细胞内 ATP 水平降低所促进的。为了使细胞离开休眠状态并复苏，需要清除蛋白聚集体并恢复蛋白稳态。我们揭示了招募功能性 DnaK-ClpB 机器的能力，这有助于以 ATP 依赖的方式进行蛋白解聚，从而决定了细菌再生长的滞后时间。更好地了解在抗生素攻击后调节细菌再生长的关键因素可能会为对抗细菌抗生素耐受性提供新的治疗策略。
