title: Comparative genomics of the IncA/C multidrug resistance plasmid family.
abstract: Multidrug resistance (MDR) plasmids belonging to the IncA/C plasmid family are widely distributed among Salmonella and other enterobacterial isolates from agricultural sources and have, at least once, also been identified in a drug-resistant Yersinia pestis isolate (IP275) from Madagascar. Here, we present the complete plasmid sequences of the IncA/C reference plasmid pRA1 (143,963 bp), isolated in 1971 from the fish pathogen Aeromonas hydrophila, and of the cryptic IncA/C plasmid pRAx (49,763 bp), isolated from Escherichia coli transconjugant D7-3, which was obtained through pRA1 transfer in 1980. Using comparative sequence analysis of pRA1 and pRAx with recent members of the IncA/C plasmid family, we show that both plasmids provide novel insights into the evolution of the IncA/C MDR plasmid family and the minimal machinery necessary for stable IncA/C plasmid maintenance. Our results indicate that recent members of the IncA/C plasmid family evolved from a common ancestor, similar in composition to pRA1, through stepwise integration of horizontally acquired resistance gene arrays into a conserved plasmid backbone. Phylogenetic comparisons predict type IV secretion-like conjugative transfer operons encoded on the shared plasmid backbones to be closely related to a group of integrating conjugative elements, which use conjugative transfer for horizontal propagation but stably integrate into the host chromosome during vegetative growth. A hipAB toxin-antitoxin gene cluster found on pRA1, which in Escherichia coli is involved in the formation of persister cell subpopulations, suggests persistence as an early broad-spectrum antimicrobial resistance mechanism in the evolution of IncA/C resistance plasmids.
authors.affiliation: Institute for Genome Sciences (IGS), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: W Florian
authors.initials: WF
authors.lastname: Fricke
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Welch
authors.forename: Patrick F
authors.initials: PF
authors.lastname: McDermott
authors.forename: Mark K
authors.initials: MK
authors.lastname: Mammel
authors.forename: J Eugene
authors.initials: JE
authors.lastname: LeClerc
authors.forename: David G
authors.initials: DG
authors.lastname: White
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cebula
authors.forename: Jacques
authors.initials: J
authors.lastname: Ravel
mesh_terms: D016980:Aeromonas hydrophila / Q000235:genetics; D000465:Algorithms; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics* / Q000502:physiology; D004926:Escherichia coli / Q000235:genetics; D023281:Genomics; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010802:Phylogeny; D010957:Plasmids / Q000235:genetics* / Q000502:physiology*; D017422:Sequence Analysis, DNA