title: (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity.
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.
authors.affiliation: Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Richardson Road, Newcastle upon Tyne NE2 4AX, UK.
authors.forename: Etienne
authors.initials: E
authors.lastname: Maisonneuve
authors.affiliation: Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Richardson Road, Newcastle upon Tyne NE2 4AX, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Castro-Camargo
authors.affiliation: Centre for Bacterial Cell Biology, Institute for Cell and Molecular Biosciences, Newcastle University, Richardson Road, Newcastle upon Tyne NE2 4AX, UK. Electronic address: kenn.gerdes@ncl.ac.uk.
authors.forename: Kenn
authors.initials: K
authors.lastname: Gerdes
mesh_terms: D000992:Antitoxins / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D006158:Guanosine Pentaphosphate / Q000378:metabolism*; D011122:Polyphosphates / Q000378:metabolism; D049070:Protease La / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000992:Antitoxins; D001427:Bacterial Toxins; D011122:Polyphosphates; D006158:Guanosine Pentaphosphate; D049070:Protease La