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Mol Cell. 2016 Apr 21;62(2):284-294. doi: 10.1016/j.molcel.2016.03.035.

Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.

Author information

1
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
2
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
3
Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
4
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871; Beijing International Center for Mathematical Research, Peking University, Beijing, China, 100871.
5
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: xie@chemistry.harvard.edu.
6
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871. Electronic address: fbai@pku.edu.cn.

Abstract

Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance.

PMID:
27105118
PMCID:
PMC4850422
DOI:
10.1016/j.molcel.2016.03.035
[Indexed for MEDLINE]
Free PMC Article

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