title: Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence.
abstract: In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxin-antitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.
authors.affiliation: Racah Institute of Physics, Center for Nanoscience and Nanotechnology, Sudarsky Center for Computational Biology, Hebrew University, Jerusalem 91904, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Rotem
authors.forename: Adiel
authors.initials: A
authors.lastname: Loinger
authors.forename: Irine
authors.initials: I
authors.lastname: Ronin
authors.forename: Irit
authors.initials: I
authors.lastname: Levin-Reisman
authors.forename: Chana
authors.initials: C
authors.lastname: Gabay
authors.forename: Noam
authors.initials: N
authors.lastname: Shoresh
authors.forename: Ofer
authors.initials: O
authors.lastname: Biham
authors.forename: Nathalie Q
authors.initials: NQ
authors.lastname: Balaban
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000992:Antitoxins / Q000235:genetics / Q000494:pharmacology; D001419:Bacteria / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics* / Q000254:growth & development / Q000502:physiology*; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics; D020512:Myopathy, Central Core / Q000235:genetics; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics; D056806:Urea Cycle Disorders, Inborn
chemical_list: D000900:Anti-Bacterial Agents; D000992:Antitoxins