title: Activation of phenotypic subpopulations in response to ciprofloxacin treatment in Acinetobacter baumannii.
abstract: The multidrug-resistant, opportunistic pathogen, Acinetobacter baumannii, has spread swiftly through hospitals worldwide. Previously, we demonstrated that A. baumannii regulates the expression of various genes in response to DNA damage. Some of these regulated genes, especially those encoding the multiple error-prone DNA polymerases, can be implicated in induced mutagenesis, leading to antibiotic resistance. Here, we further explore the DNA damage-inducible system at the single cell level using chromosomal transcriptional reporters for selected DNA damage response genes. We found the genes examined respond in a bimodal fashion to ciprofloxacin treatment, forming two phenotypic subpopulations: induced and uninduced. This bimodal response to ciprofloxacin treatment in A. baumannii is unique and quite different than the Escherichia coli paradigm. The subpopulations are not genetically different, with each subpopulation returning to a starting state and differentiating with repeated treatment. We then identified a palindromic motif upstream of certain DNA damage response genes, and have shown alterations to this sequence to diminish the bimodal induction in response to DNA damaging treatment. Lastly, we are able to show a biological advantage for a bimodal response, finding that one subpopulation survives ciprofloxacin treatment better than the other.
authors.affiliation: Department of Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Macguire
authors.forename: Meining Carly
authors.initials: MC
authors.lastname: Ching
authors.forename: Brett H
authors.initials: BH
authors.lastname: Diamond
authors.forename: Alexey
authors.initials: A
authors.lastname: Kazakov
authors.forename: Pavel
authors.initials: P
authors.lastname: Novichkov
authors.forename: Veronica G
authors.initials: VG
authors.lastname: Godoy
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002939:Ciprofloxacin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D017930:Genes, Reporter / Q000235:genetics; D016680:Genome, Bacterial; D055029:Inverted Repeat Sequences; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D013014:SOS Response, Genetics
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002939:Ciprofloxacin; D008741:Methyl Methanesulfonate