1. Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.
- Author
-
Pu Y, Zhao Z, Li Y, Zou J, Ma Q, Zhao Y, Ke Y, Zhu Y, Chen H, Baker MAB, Ge H, Sun Y, Xie XS, and Bai F
- Subjects
- Anti-Bacterial Agents metabolism, Bacterial Outer Membrane Proteins genetics, Biological Transport, Boron Compounds metabolism, Colony Count, Microbial, Dose-Response Relationship, Drug, Escherichia coli genetics, Escherichia coli growth & development, Escherichia coli metabolism, Escherichia coli Proteins genetics, Gene Expression Regulation, Bacterial, Genotype, High-Throughput Nucleotide Sequencing, Membrane Transport Proteins genetics, Microbial Viability drug effects, Mutation, Optical Imaging, Penicillins metabolism, Phenotype, Time Factors, Up-Regulation, Anti-Bacterial Agents pharmacology, Bacterial Outer Membrane Proteins metabolism, Boron Compounds pharmacology, Drug Resistance, Bacterial genetics, Escherichia coli drug effects, Escherichia coli Proteins metabolism, Membrane Transport Proteins metabolism, Penicillins pharmacology
- 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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF