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Mol Cell. 2019 Jan 3;73(1):143-156.e4. doi: 10.1016/j.molcel.2018.10.022. Epub 2018 Nov 21.

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

Author information

1
Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
2
Department of Physics and Graduate Institute of Biophysics, National Central University, Jhong-Li, Taoyuan 32001, Republic of China.
3
Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, Beijing 100069, China.
4
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.
5
Department of Physics, University of York, York YO10, UK; Department of Biology, University of York, York YO10, UK.
6
Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: fbai@pku.edu.cn.

Abstract

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.

KEYWORDS:

ATP; DnaK-ClpB complex; bacterial antibiotic tolerance; cell resuscitation; dormancy depth; persisters; protein aggregates; viable but non-culturable cells

PMID:
30472191
DOI:
10.1016/j.molcel.2018.10.022
[Indexed for MEDLINE]

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