title: Bacterial evolution of antibiotic hypersensitivity.
abstract: The evolution of resistance to a single antibiotic is frequently accompanied by increased resistance to multiple other antimicrobial agents. In sharp contrast, very little is known about the frequency and mechanisms underlying collateral sensitivity. In this case, genetic adaptation under antibiotic stress yields enhanced sensitivity to other antibiotics. Using large-scale laboratory evolutionary experiments with Escherichia coli, we demonstrate that collateral sensitivity occurs frequently during the evolution of antibiotic resistance. Specifically, populations adapted to aminoglycosides have an especially low fitness in the presence of several other antibiotics. Whole-genome sequencing of laboratory-evolved strains revealed multiple mechanisms underlying aminoglycoside resistance, including a reduction in the proton-motive force (PMF) across the inner membrane. We propose that as a side effect, these mutations diminish the activity of PMF-dependent major efflux pumps (including the AcrAB transporter), leading to hypersensitivity to several other antibiotics. More generally, our work offers an insight into the mechanisms that drive the evolution of negative trade-offs under antibiotic selection.
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Center, Szeged, Hungary.
authors.forename: Viktória
authors.initials: V
authors.lastname: Lázár
authors.forename: Gajinder
authors.initials: G
authors.lastname: Pal Singh
authors.forename: Réka
authors.initials: R
authors.lastname: Spohn
authors.forename: István
authors.initials: I
authors.lastname: Nagy
authors.forename: Balázs
authors.initials: B
authors.lastname: Horváth
authors.forename: Mónika
authors.initials: M
authors.lastname: Hrtyan
authors.forename: Róbert
authors.initials: R
authors.lastname: Busa-Fekete
authors.forename: Balázs
authors.initials: B
authors.lastname: Bogos
authors.forename: Orsolya
authors.initials: O
authors.lastname: Méhi
authors.forename: Bálint
authors.initials: B
authors.lastname: Csörgő
authors.forename: György
authors.initials: G
authors.lastname: Pósfai
authors.forename: Gergely
authors.initials: G
authors.lastname: Fekete
authors.forename: Balázs
authors.initials: B
authors.lastname: Szappanos
authors.forename: Balázs
authors.initials: B
authors.lastname: Kégl
authors.forename: Balázs
authors.initials: B
authors.lastname: Papp
authors.forename: Csaba
authors.initials: C
authors.lastname: Pál
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D005075:Biological Evolution; D001692:Biological Transport; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004352:Drug Resistance, Microbial / Q000235:genetics; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics* / Q000378:metabolism; D016680:Genome, Bacterial; D059014:High-Throughput Nucleotide Sequencing; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012641:Selection, Genetic
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins