title: Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic Tolerance.
abstract: Within bacterial populations, a small fraction of persister cells is transiently capable of surviving exposure to lethal doses of antibiotics. As a bet-hedging strategy, persistence levels are determined both by stochastic induction and by environmental stimuli called responsive diversification. Little is known about the mechanisms that link the low frequency of persisters to environmental signals. Our results support a central role for the conserved GTPase Obg in determining persistence in Escherichia coli in response to nutrient starvation. Obg-mediated persistence requires the stringent response alarmone (p)ppGpp and proceeds through transcriptional control of the hokB-sokB type I toxin-antitoxin module. In individual cells, increased Obg levels induce HokB expression, which in turn results in a collapse of the membrane potential, leading to dormancy. Obg also controls persistence in Pseudomonas aeruginosa and thus constitutes a conserved regulator of antibiotic tolerance. Combined, our findings signify an important step toward unraveling shared genetic mechanisms underlying persistence.
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Verstraeten
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Wouter Joris
authors.initials: WJ
authors.lastname: Knapen
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Cyrielle Ines
authors.initials: CI
authors.lastname: Kint
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Veerle
authors.initials: V
authors.lastname: Liebens
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Van den Bergh
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Liselot
authors.initials: L
authors.lastname: Dewachter
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Joran Elie
authors.initials: JE
authors.lastname: Michiels
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Molecular Imaging and Photonics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Charlotte Claudia
authors.initials: CC
authors.lastname: David
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Fierro
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium; Department of Plant Biotechnology and Bioinformatics, Universiteit Gent, 9052 Ghent, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Marchal
authors.affiliation: Statistics Section, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Beirlant
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Structural Biology Research Center, VIB, 1050 Brussels, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Versées
authors.affiliation: Molecular Imaging and Photonics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Hofkens
authors.affiliation: Departments of Mathematics and Computer Science, Université Libre de Bruxelles, 1050 Brussels, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fauvart
authors.affiliation: Centre of Microbial and Plant Genetics, KU Leuven - University of Leuven, 3001 Leuven, Belgium. Electronic address: jan.michiels@biw.kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics*; D001427:Bacterial Toxins / Q000096:biosynthesis* / Q000235:genetics; D002462:Cell Membrane / Q000502:physiology; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D004926:Escherichia coli / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000096:biosynthesis* / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics*; D008564:Membrane Potentials / Q000235:genetics; D008826:Microbial Sensitivity Tests; D017434:Protein Structure, Tertiary / Q000235:genetics; D011550:Pseudomonas aeruginosa / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; C000601825:HokB protein, E coli; C090542:Obg GTP-binding protein, Bacteria; D019204:GTP-Binding Proteins