ATP-Dependent Dynamic Protein Aggregation Regulates Bacterial Dormancy Depth Critical for Antibiotic Tolerance

• Published in: Molecular cell 2019-01, Vol.73 (1), p.143-156.e4
• Main Authors: Pu, Yingying, Li, Yingxing, Jin, Xin, Tian, Tian, Ma, Qi, Zhao, Ziyi, Lin, Ssu-yuan, Chen, Zhanghua, Li, Binghui, Yao, Guang, Leake, Mark C., Lo, Chien-Jung, Bai, Fan
• Format: Article
• Language: English
• Subjects: antibiotic resistance; antibiotics; ATP; bacterial antibiotic tolerance; cell resuscitation; DnaK-ClpB complex; dormancy; dormancy depth; persisters; protein aggregates; regrowth; therapeutics; viable but non-culturable cells
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.10.022

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. [Display omitted] •The degree of drug-tolerant cells being dormant can be measured by “dormancy depth”•Cellular dark foci, proved to be protein aggresomes, indicate dormancy depth•Depletion of intracellular ATP is the major force driving aggresomes formation•DnaK is vital in the disaggregation of aggresomes when a dormant cell resuscitates In this work, Pu et al. introduced a concept of “dormancy depth” that provides a unifying framework for understanding both persisters and viable but non-culturable cells. Subsequent mechanistic investigations revealed how ATP-dependent dynamic protein aggregation regulates cellular dormancy and resuscitation, the fine control of which facilitates bacterial drug tolerance.