|Welch, Timothy - Tim|
Submitted to: Journal of Bacteriology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/29/2009
Publication Date: 5/29/2009
Citation: Fricle, F., Welch, T.J., Mcdermott, P., Mammel, M., Leclerc, E., White, D., Cebula, T., Ravel, J. 2009. Comparative genomics of the IncA/C multidrug resistance plasmid family. Journal of Bacteriology. 191(15):4750-4757.
Interpretive Summary: We have recently discovered and characterized a large family of self-transmissible IncA/C multidrug resistance (MDR) plasmids. These plasmids are widely distributed in bacteria associated with agricultural animal pathogens and have been found in clinical isolates of several human pathogens including Yersinia pestis, Vibrio cholerae and Salmonella. In this study, we present the complete DNA sequence of the first identified IncA/C plasmid (pRA1) which was isolated in Japan in 1971. Comparing the sequence of pRA1 to contemporary IncA/C plasmids revealed that this plasmid family evolved from a common ancestor through stepwise integration of acquired resistance gene cassettes into a conserved plasmid backbone. This work provides insight into the mechanisms by which these important plasmids have acquired and spread antimicrobial resistance.
Technical 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 E. 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 early evolution 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 cassettes 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 (ICEs), 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-range antimicrobial resistance mechanism in the evolution of IncA/C resistance plasmids.