title: Selection of resistant bacteria at very low antibiotic concentrations.
abstract: The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Gullberg
authors.forename: Sha
authors.initials: S
authors.lastname: Cao
authors.forename: Otto G
authors.initials: OG
authors.lastname: Berg
authors.forename: Carolina
authors.initials: C
authors.lastname: Ilbäck
authors.forename: Linus
authors.initials: L
authors.lastname: Sandegren
authors.forename: Diarmaid
authors.initials: D
authors.lastname: Hughes
authors.forename: Dan I
authors.initials: DI
authors.lastname: Andersson
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001483:Base Sequence; D004305:Dose-Response Relationship, Drug; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000502:physiology; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development*; D008954:Models, Biological; D008969:Molecular Sequence Data; D012486:Salmonella typhimurium / Q000235:genetics / Q000254:growth & development*; D012641:Selection, Genetic / Q000187:drug effects* / Q000502:physiology
chemical_list: D000900:Anti-Bacterial Agents