Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells

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

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.

Publication types

  • Video-Audio Media
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Outer Membrane Proteins / genetics
  • Bacterial Outer Membrane Proteins / metabolism*
  • Biological Transport
  • Boron Compounds / metabolism
  • Boron Compounds / pharmacology*
  • Colony Count, Microbial
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial* / genetics
  • Escherichia coli / drug effects*
  • Escherichia coli / genetics
  • Escherichia coli / growth & development
  • Escherichia coli / metabolism
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Gene Expression Regulation, Bacterial
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Microbial Viability / drug effects
  • Mutation
  • Optical Imaging
  • Penicillins / metabolism
  • Penicillins / pharmacology*
  • Phenotype
  • Time Factors
  • Up-Regulation

Substances

  • Anti-Bacterial Agents
  • BOCILLIN FL
  • Bacterial Outer Membrane Proteins
  • Boron Compounds
  • Escherichia coli Proteins
  • Membrane Transport Proteins
  • Penicillins
  • tolC protein, E coli