RT Journal Article
SR Electronic
T1 Nested Russian Doll-like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene <em>bla</em><sub>KPC</sub>
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 033522
DO 10.1101/033522
A1 Anna E. Sheppard
A1 Nicole Stoesser
A1 Daniel J. Wilson
A1 Robert Sebra
A1 Andrew Kasarskis
A1 Luke W. Anson
A1 Adam Giess
A1 Louise J. Pankhurst
A1 Alison Vaughan
A1 Christopher J. Grim
A1 Heather L. Cox
A1 Anthony J. Yeh
A1 the Modernising Medical Microbiology (MMM) Informatics Group
A1 Costi D. Sifri
A1 A. Sarah Walker
A1 Tim E. Peto
A1 Derrick W. Crook
A1 AmyJ. Mathers
YR 2015
UL http://biorxiv.org/content/early/2015/12/02/033522.abstract
AB The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort in this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms including conjugation and transposition, however the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is currently unknown. Using a combination of short- and long-read whole genome sequencing of 281 blaKPC-positive Enterobacteriaceae isolated from a single hospital over five years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of blaKPC occurs at multiple nested genetic levels, with transmission of blaKPC strains between individuals, frequent transfer of blaKPC plasmids between strains/species, and frequent transposition of the blaKPC transposon Tn4401 between plasmids. We also identify a common insertion site for Tn4401 within various Tn2-like elements, suggesting that homologous recombination between Tn2-like elements has enhanced the spread of Tn4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this with the use of reference-based methods. We also demonstrate that as a consequence of the genetic mobility observed herein, plasmid structures can be extremely dynamic, and therefore these reference-based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that non-clonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance.Importance Increasing antibiotic resistance is a major threat to human health, as highlighted by the recent emergence of multi-drug resistant “superbugs”. Here, we tracked how one important multi-drug resistance gene spread in a single hospital over five years. This revealed high levels of resistance gene mobility to multiple bacterial species, which was facilitated by various different genetic mechanisms. The mobility occurred at multiple nested genetic levels, analogous to a Russian doll set where smaller dolls may be carried along inside larger dolls. Our results challenge traditional views that drug-resistance outbreaks are due to transmission of a single pathogenic strain. Instead, outbreaks can be “gene-based”, and we must therefore focus on tracking specific resistance genes and their context rather than only specific bacteria.