title: Strength of selection pressure is an important parameter contributing to the complexity of antibiotic resistance evolution.
abstract: Revealing the genetic changes responsible for antibiotic resistance can be critical for developing novel antibiotic therapies. However, systematic studies correlating genotype to phenotype in the context of antibiotic resistance have been missing. In order to fill in this gap, we evolved 88 isogenic Escherichia coli populations against 22 antibiotics for 3 weeks. For every drug, two populations were evolved under strong selection and two populations were evolved under mild selection. By quantifying evolved populations' resistances against all 22 drugs, we constructed two separate cross-resistance networks for strongly and mildly selected populations. Subsequently, we sequenced representative colonies isolated from evolved populations for revealing the genetic basis for novel phenotypes. Bacterial populations that evolved resistance against antibiotics under strong selection acquired high levels of cross-resistance against several antibiotics, whereas other bacterial populations evolved under milder selection acquired relatively weaker cross-resistance. In addition, we found that strongly selected strains against aminoglycosides became more susceptible to five other drug classes compared with their wild-type ancestor as a result of a point mutation on TrkH, an ion transporter protein. Our findings suggest that selection strength is an important parameter contributing to the complexity of antibiotic resistance problem and use of high doses of antibiotics to clear infections has the potential to promote increase of cross-resistance in clinics.
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Tugce
authors: T
authors: Oz
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Aysegul
authors: A
authors: Guvenek
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Sadik
authors: S
authors: Yildiz
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Enes
authors: E
authors: Karaboga
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Yusuf Talha
authors: YT
authors: Tamer
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Nirva
authors: N
authors: Mumcuyan
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Vedat Burak
authors: VB
authors: Ozan
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Gizem Hazal
authors: GH
authors: Senturk
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey.
authors: Murat
authors: M
authors: Cokol
authors: Department of Ecology and Evolutionary Biology, University of California, Los Angeles.
authors: Pamela
authors: P
authors: Yeh
authors: Faculty of Engineering and Natural Sciences, Sabanci University, Istanbul, Turkey erdaltoprak@sabanciuniv.edu erdaltoprak@gmail.com.
authors: Erdal
authors: E
authors: Toprak
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000617:Aminoglycosides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D024901:Drug Resistance, Multiple, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000235:genetics; D019143:Evolution, Molecular; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D017354:Point Mutation; D015221:Potassium Channels / Q000235:genetics; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
chemical_list: D018528:ATP-Binding Cassette Transporters; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D015221:Potassium Channels; C443122:TrkH protein, E coli
keywords: antibiotic resistance; antibiotic susceptibility; cross-resistance; evolution; genotyping; whole-genome sequencing