(p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity

Cell. 2013 Aug 29;154(5):1140-1150. doi: 10.1016/j.cell.2013.07.048.

Abstract

Persistence refers to the phenomenon in which isogenic populations of antibiotic-sensitive bacteria produce rare cells that transiently become multidrug tolerant. Whether slow growth in a rare subset of cells underlies the persistence phenotype has not be examined in wild-type bacteria. Here, we show that an exponentially growing population of wild-type Escherichia coli cells produces rare cells that stochastically switch into slow growth, that the slow-growing cells are multidrug tolerant, and that they are able to resuscitate. The persistence phenotype depends hierarchically on the signaling nucleotide (p)ppGpp, Lon protease, inorganic polyphosphate, and toxin-antitoxins. We show that the level of (p)ppGpp varies stochastically in a population of exponentially growing cells and that the high (p)ppGpp level in rare cells induces slow growth and persistence. (p)ppGpp triggers slow growth by activating toxin-antitoxin loci through a regulatory cascade depending on inorganic polyphosphate and Lon protease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Antitoxins / metabolism
  • Bacterial Toxins / metabolism
  • Drug Resistance, Multiple, Bacterial
  • Escherichia coli / drug effects
  • Escherichia coli / growth & development*
  • Escherichia coli / metabolism*
  • Guanosine Pentaphosphate / metabolism*
  • Polyphosphates / metabolism
  • Protease La / metabolism
  • Transcription, Genetic

Substances

  • Antitoxins
  • Bacterial Toxins
  • Polyphosphates
  • Guanosine Pentaphosphate
  • Protease La