Bacterial persistence is an active σS stress response to metabolic flux limitation

Jakub Leszek Radzikowski, Silke Vedelaar, David Siegel, Álvaro Dario Ortega, Alexander Schmidt, Matthias Heinemann*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

78 Citations (Scopus)
236 Downloads (Pure)

Abstract

While persisters are a health threat due to their transient antibiotic tolerance, little is known about their phenotype and what actually causes persistence. Using a new method for persister generation and high-throughput methods, we comprehensively mapped the molecular phenotype of Escherichia coli during the entry and in the state of persistence in nutrient-rich conditions. The persister proteome is characterized by sigma(S)-mediated stress response and a shift to catabolism, a proteome that starved cells tried to but could not reach due to absence of a carbon and energy source. Metabolism of persisters is geared toward energy production, with depleted metabolite pools. We developed and experimentally verified a model, in which persistence is established through a system-level feedback: Strong perturbations of metabolic homeostasis cause metabolic fluxes to collapse, prohibiting adjustments toward restoring homeostasis. This vicious cycle is stabilized and modulated by high ppGpp levels, toxin/anti-toxin systems, and the sigma(S)-mediated stress response. Our system-level model consistently integrates past findings with our new data, thereby providing an important basis for future research on persisters.

Original languageEnglish
Article number882
Pages (from-to)1-18
Number of pages18
JournalMolecular Systems Biology
Volume12
Issue number9
DOIs
Publication statusPublished - Sep-2016

Keywords

  • Escherichia coli
  • metabolism
  • persistence
  • proteomics
  • stress response
  • MEDIATE ANTIBIOTIC TOLERANCE
  • ESCHERICHIA-COLI
  • GENE-EXPRESSION
  • RIBONUCLEIC-ACID
  • MESSENGER-RNA
  • STARVATION
  • CELLS
  • GROWTH
  • PROTEIN
  • PPGPP

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