title: Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistence.
abstract: The evolution of antibiotic resistance is a major threat to society and has been predicted to lead to 10 million casualties annually by 2050(1). Further aggravating the problem, multidrug tolerance in bacteria not only relies on the build-up of resistance mutations, but also on some cells epigenetically switching to a non-growing antibiotic-tolerant 'persister' state(2-6). Yet, despite its importance, we know little of how persistence evolves in the face of antibiotic treatment(7). Our evolution experiments in Escherichia coli demonstrate that extremely high levels of multidrug tolerance (20-100%) are achieved by single point mutations in one of several genes and readily emerge under conditions approximating clinical, once-daily dosing schemes. In contrast, reversion to low persistence in the absence of antibiotic treatment is relatively slow and only partially effective. Moreover, and in support of previous mathematical models(8-10), we show that bacterial persistence quickly adapts to drug treatment frequency and that the observed rates of switching to the persister state can be understood in the context of 'bet-hedging' theory. We conclude that persistence is a major component of the evolutionary response to antibiotics that urgently needs to be considered in both diagnostic testing and treatment design in the battle against multidrug tolerance.
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Bram
authors: B
authors: Van den Bergh
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Joran E
authors: http://orcid.org/0000-0003-2169-3507
authors: JE
authors: Michiels
authors: KU Leuven - University of Leuven, Laboratory of Socioecology and Social Evolution, B-3000 Leuven, Belgium.
authors: Tom
authors: T
authors: Wenseleers
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Etthel M
authors: EM
authors: Windels
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Pieterjan Vanden
authors: PV
authors: Boer
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Donaat
authors: http://orcid.org/0000-0001-5822-1250
authors: D
authors: Kestemont
authors: KU Leuven - University of Leuven, Laboratory of Aquatic Ecology, Evolution and Conservation, B-3000 Leuven, Belgium.
authors: Luc
authors: L
authors: De Meester
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.|Flanders Institute for Biotechnology - VIB, Laboratory for Systems Biology, B-3001 Leuven, Belgium.
authors: Kevin J
authors: KJ
authors: Verstrepen
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Natalie
authors: N
authors: Verstraeten
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.|Department of Life Science Technologies, imec, Smart Systems and Emerging Technologies Unit, B-3001 Leuven, Belgium.
authors: Maarten
authors: M
authors: Fauvart
authors: KU Leuven - University of Leuven, Centre of Microbial and Plant Genetics, B-3001 Leuven, Belgium.
authors: Jan
authors: http://orcid.org/0000-0002-3043-3259
authors: J
authors: Michiels
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004361:Drug Tolerance; D004363:Drug Utilization; D004926:Escherichia coli / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents