title: Bacterial persistence is an active σS stress response to metabolic flux limitation.
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 σ(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 σ(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.
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Jakub Leszek
authors.initials: JL
authors.lastname: Radzikowski
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Silke
authors.initials: S
authors.lastname: Vedelaar
authors.affiliation: Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.
authors.forename: Álvaro Dario
authors.initials: ÁD
authors.lastname: Ortega
authors.affiliation: Biozentrum, University of Basel, Basel, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Molecular Systems Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands m.heinemann@rug.nl.
authors.forename: Matthias
authors.identifier: 0000-0002-5512-9077
authors.initials: M
authors.lastname: Heinemann
mesh_terms: D003470:Culture Media / Q000737:chemistry; D004361:Drug Tolerance; D004926:Escherichia coli / Q000254:growth & development* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D008660:Metabolism; D040901:Proteomics / Q000379:methods*; D013312:Stress, Physiological
chemical_list: D003470:Culture Media; D029968:Escherichia coli Proteins
keywords: Escherichia coli; metabolism; persistence; proteomics; stress response