Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.
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.
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yingying
Y
Pu
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Zhilun
Z
Zhao
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yingxing
Y
Li
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Jin
J
Zou
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Qi
Q
Ma
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yanna
Y
Zhao
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yuehua
Y
Ke
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yun
Y
Zhu
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Huiyi
H
Chen
Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
Matthew A B
MAB
Baker
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.
Hao
H
Ge
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871.
Yujie
Y
Sun
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.
Xiaoliang Sunney
XS
Xie
Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China, 100871. Electronic address: fbai@pku.edu.cn.
Fan
F
Bai
D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D001896:Boron Compounds / Q000378:metabolism / Q000494:pharmacology*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D061848:Optical Imaging; D010406:Penicillins / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D013997:Time Factors; D015854:Up-Regulation
D000900:Anti-Bacterial Agents; C118961:BOCILLIN FL; D001425:Bacterial Outer Membrane Proteins; D001896:Boron Compounds; D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; D010406:Penicillins; C073126:tolC protein, E coli