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

Molecular and genomic surveillance systems for bacterial pathogens currently rely on tracking clonally evolving lineages. By contrast, plasmids are usually excluded or analyzed with low-resolution techniques, despite being the primary vectors of antibiotic resistance genes across many key pathogens....

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 40; pp. 25043 - 25054
Main Authors David, Sophia, Cohen, Victoria, Reuter, Sandra, Sheppar, Anna E., Giani, Tommaso, Parkhill, Julian, Rossolini, Gian Maria, Feil, Edward J., Grundman, Hajo, Aanensen, David M.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 06.10.2020
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Summary:Molecular and genomic surveillance systems for bacterial pathogens currently rely on tracking clonally evolving lineages. By contrast, plasmids are usually excluded or analyzed with low-resolution 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, bla OXA-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, bla VIM and bla NDM genes have spread via transient associations of many diverse plasmids with numerous lineages. Third, bla KPC 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 bla KPC. 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.
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Author contributions: S.D. and D.M.A. designed research; S.D. and V.C. performed research; E.S.C.-P.E.W.G. and E.S.G.E.M. contributed new reagents/analytic tools; S.D., S.R., A.E.S., T.G., J.P., G.M.R., E.J.F., H.G., and D.M.A. analyzed data; E.S.C.-P.E.W.G. collected the bacterial isolates and epidemiological data; E.S.G.E.M. facilitated the training and capacity building for the collection of bacterial isolates; and S.D., G.M.R., E.J.F., H.G., and D.M.A. wrote the paper.
Edited by Rita R. Colwell, University of Maryland, College Park, MD, and approved August 17, 2020 (received for review February 23, 2020)
3H.G. and D.M.A. contributed equally to this work.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2003407117