Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Eitan Rotem, Adiel Loinger, Irine Ronin, Irit Levin-Reisman, Chana Gabay, Noam Shoresh, Ofer Biham, Nathalie Q. Balaban

Research output: Contribution to journalArticlepeer-review

267 Scopus citations

Abstract

In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxin-antitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.

Original languageAmerican English
Pages (from-to)12541-12546
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number28
DOIs
StatePublished - 13 Jul 2010

Keywords

  • Single-cell
  • Stochasticity
  • Systems biology

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