1. Evolutionary Biology
  2. Microbiology and Infectious Disease
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Genetic determinants facilitating the evolution of resistance to carbapenem antibiotics

Research Article
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Cite this article as: eLife 2021;10:e67310 doi: 10.7554/eLife.67310

Abstract

In this era of rising antibiotic resistance, in contrast to our increasing understanding of mechanisms that cause resistance, our understanding of mechanisms that influence the propensity to evolve resistance remains limited. Here, we identified genetic factors that facilitate the evolution of resistance to carbapenems, the antibiotic of 'last resort,' in Klebsiella pneumoniae, the major carbapenem resistant species. In clinical isolates, we found that high-level transposon insertional mutagenesis plays an important role in contributing to high-level resistance frequencies in several major and emerging carbapenem-resistant lineages. A broader spectrum of resistance-conferring mutations for select carbapenems such as ertapenem also enables higher resistance frequencies and importantly, creates stepping-stones to achieve high-level resistance to all carbapenems. These mutational mechanisms can contribute to the evolution of resistance, in conjunction with the loss of systems that restrict horizontal resistance gene uptake, such as the CRISPR-Cas system. Given the need for greater antibiotic stewardship, these findings argue that in addition to considering the current efficacy of an antibiotic for a clinical isolate in antibiotic selection, considerations of future efficacy are also important. The genetic background of a clinical isolate and the exact antibiotic identity can and should also be considered as it is a determinant of a strain's propensity to become resistant. Together, these findings thus provide a molecular framework for understanding acquisition of carbapenem resistance in K. pneumoniae with important implications for diagnosing and treating this important class of pathogens.

Data availability

All data generated or analyzed during this study are included in this article and in the supplementary tables. Sequencing data is deposited to NCBI under the accession number PRJNA670748.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Peijun Ma

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7670-7016
  2. Lorrie L He

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alejandro Pironti

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hannah H Laibinis

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christoph M Ernst

    Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Abigail L Manson

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3800-0714
  7. Roby P Bhattacharyya

    Infectious Diseases and Micriobiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6955-5088
  8. Ashlee M Earl

    Infectious Disease and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jonathan Livny

    Genome Sequencing & Analysis Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Deborah Hung

    Infectious Diseases and Microbiome Program, The Broad Institute of MIT and Harvard, Cambridge, United States
    For correspondence
    dhung@broadinstitute.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4262-0673

Funding

National Institute of Allergy and Infectious Diseases (5R01AI117043-05)

  • Deborah Hung

National Institute of Allergy and Infectious Diseases (U19AI110818)

  • Ashlee M Earl

Anita and Josh Bekenstein Gram Negative Gift

  • Deborah Hung

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Antonis Rokas, Vanderbilt University, United States

Publication history

  1. Received: February 8, 2021
  2. Accepted: April 15, 2021
  3. Accepted Manuscript published: April 19, 2021 (version 1)
  4. Version of Record published: April 27, 2021 (version 2)

Copyright

© 2021, Ma et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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