title: Emergence of antibiotic resistance from multinucleated bacterial filaments.
abstract: Bacteria can rapidly evolve resistance to antibiotics via the SOS response, a state of high-activity DNA repair and mutagenesis. We explore here the first steps of this evolution in the bacterium Escherichia coli. Induction of the SOS response by the genotoxic antibiotic ciprofloxacin changes the E. coli rod shape into multichromosome-containing filaments. We show that at subminimal inhibitory concentrations of ciprofloxacin the bacterial filament divides asymmetrically repeatedly at the tip. Chromosome-containing buds are made that, if resistant, propagate nonfilamenting progeny with enhanced resistance to ciprofloxacin as the parent filament dies. We propose that the multinucleated filament creates an environmental niche where evolution can proceed via generation of improved mutant chromosomes due to the mutagenic SOS response and possible recombination of the new alleles between chromosomes. Our data provide a better understanding of the processes underlying the origin of resistance at the single-cell level and suggest an analogous role to the eukaryotic aneuploidy condition in cancer.
authors.affiliation: Department of Physics, Princeton University, Princeton, NJ 08544-0708;
authors.forename: Julia
authors.initials: J
authors.lastname: Bos
authors.affiliation: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801-3080; and.
authors.forename: Qiucen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Physics, Princeton University, Princeton, NJ 08544-0708;
authors.forename: Saurabh
authors.initials: S
authors.lastname: Vyawahare
authors.affiliation: Departments of Molecular and Human Genetics, Biochemistry and Molecular Biology, and Molecular Virology and Microbiology, and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rogers
authors.affiliation: Departments of Molecular and Human Genetics, Biochemistry and Molecular Biology, and Molecular Virology and Microbiology, and the Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Rosenberg
authors.affiliation: Department of Physics, Princeton University, Princeton, NJ 08544-0708; austin@princeton.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Austin
mesh_terms: D060049:Asymmetric Cell Division / Q000187:drug effects; D002876:Chromosomes, Bacterial / Q000378:metabolism; D002939:Ciprofloxacin / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000187:drug effects; D004926:Escherichia coli / Q000166:cytology* / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D008954:Models, Biological; D017422:Sequence Analysis, DNA
chemical_list: D002939:Ciprofloxacin
keywords: SOS response; antibiotic resistance; evolution; filamentation; mutation