Integrated chromosomal and plasmid sequence analyses reveal diverse modes of carbapenemase gene spread among Klebsiella pneumoniae

Sophia David, Victoria Cohen, Sandra Reuter, Anna E. Sheppard, Tommaso Giani, Julian Parkhill, Gian Maria Rossolini, Edward J. Feil, Hajo Grundmann, David M. Aanensen

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77 Citations (SciVal)


Molecular and genomic surveillance systems for bacterial pathogens currently rely on tracking clonally evolving lineages. By contrast, plasmids are usually excluded or analyzed with lowresolution techniques, despite being the primary vectors of antibiotic resistance genes across many key pathogens. Here, we used a combination of long- and short-read sequence data of Klebsiella pneumoniae isolates (n = 1,717) from a European survey to perform an integrated, continent-wide study of chromosomal and plasmid diversity. This revealed three contrasting modes of dissemination used by carbapenemase genes, which confer resistance to last-line carbapenems. First, blaOXA-48-like genes have spread primarily via the single epidemic pOXA-48-like plasmid, which emerged recently in clinical settings and spread rapidly to numerous lineages. Second, blaVIM and blaNDM genes have spread via transient associations of many diverse plasmids with numerous lineages. Third, blaKPC genes have transmitted predominantly by stable association with one successful clonal lineage (ST258/512) yet have been mobilized among diverse plasmids within this lineage. We show that these plasmids, which include pKpQIL-like and IncX3 plasmids, have a long association (and are coevolving) with the lineage, although frequent recombination and rearrangement events between them have led to a complex array of mosaic plasmids carrying blaKPC. Taken altogether, these results reveal the diverse trajectories of antibiotic resistance genes in clinical settings, summarized as using one plasmid/multiple lineages, multiple plasmids/multiple lineages, and multiple plasmids/one lineage. Our study provides a framework for the much needed incorporation of plasmid data into genomic surveillance systems, an essential step toward a more comprehensive understanding of resistance spread.

Original languageEnglish
Pages (from-to)25043-25054
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number40
Early online date23 Sept 2020
Publication statusPublished - 6 Oct 2020

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank the Pathogen Informatics team and the DNA Pipelines Long read team at the Wellcome Sanger Institute for their contribution to the study. This work was funded by Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Wellcome Grants 098051 and 099202 and National Institute for Health Research (NIHR) Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance Grant NIHR 16/136/111. The EuSCAPE project was funded by the European Centre for Disease Prevention and Control (ECDC) through Specific Frame-work Contract ECDC/2012/055 following an open call for tender (OJ/25/04/ 2012-PROC/2012/036).

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Copyright 2021 Elsevier B.V., All rights reserved.


  • Carbapenem resistance
  • Carbapenemase genes
  • Genomics
  • Klebsiella pneumoniae
  • Plasmids

ASJC Scopus subject areas

  • General


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