title: Computational Methods to Model Persistence.
abstract: Bacterial persister cells are dormant cells, tolerant to multiple antibiotics, that are involved in several chronic infections. Toxin-antitoxin modules play a significant role in the generation of such persister cells. Toxin-antitoxin modules are small genetic elements, omnipresent in the genomes of bacteria, which code for an intracellular toxin and its neutralizing antitoxin. In the past decade, mathematical modeling has become an important tool to study the regulation of toxin-antitoxin modules and their relation to the emergence of persister cells. Here, we provide an overview of several numerical methods to simulate toxin-antitoxin modules. We cover both deterministic modeling using ordinary differential equations and stochastic modeling using stochastic differential equations and the Gillespie method. Several characteristics of toxin-antitoxin modules such as protein production and degradation, negative autoregulation through DNA binding, toxin-antitoxin complex formation and conditional cooperativity are gradually integrated in these models. Finally, by including growth rate modulation, we link toxin-antitoxin module expression to the generation of persister cells.
authors.affiliation: Structural Biology Research Center, VIB, Brussels, Belgium.|Department of Biotechnology (DBIT), Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vandervelde
authors.affiliation: Structural Biology Research Center, VIB, Brussels, Belgium.|Department of Biotechnology (DBIT), Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.
authors.forename: Remy
authors.initials: R
authors.lastname: Loris
authors.affiliation: Applied Physics Research Group (APHY), Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Danckaert
authors.affiliation: Applied Physics Research Group (APHY), Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.|Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
authors.forename: Lendert
authors.initials: L
authors.lastname: Gelens
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001419:Bacteria / Q000187:drug effects / Q000254:growth & development; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D019295:Computational Biology / Q000379:methods*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D006801:Humans
chemical_list: D000900:Anti-Bacterial Agents
keywords: Gillespie; Modeling; ODE; Persister; Stochastic; Toxin–antitoxin