RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates

  1. Samantha G Palace
  2. Yi Wang
  3. Daniel H F Rubin
  4. Michael A Welsh
  5. Tatum D Mortimer
  6. Kevin Cole
  7. David W Eyre
  8. Suzanne Walker
  9. Yonatan H Grad  Is a corresponding author
  1. Harvard TH Chan School of Public Health, United States
  2. Harvard Medical School, United States
  3. Royal Sussex County Hospital, United Kingdom
  4. University of Oxford, United Kingdom

Abstract

Increasing Neisseria gonorrhoeae resistance to ceftriaxone, the last antibiotic recommended for empiric gonorrhea treatment, poses an urgent public health threat. However, the genetic basis of reduced susceptibility to ceftriaxone is not completely understood: while most ceftriaxone resistance in clinical isolates is caused by target site mutations in penA, others lack these mutations. We show that penA-independent ceftriaxone resistance has evolved multiple times through distinct mutations in rpoB and rpoD. We identify five mutations in these genes that each increase resistance to ceftriaxone, including one mutation that arose independently in two lineages, and show that clinical isolates from multiple lineages are a single nucleotide change from ceftriaxone resistance. These RNA polymerase mutations result in large-scale transcriptional changes without altering susceptibility to other antibiotics, reducing growth rate, or deranging cell morphology. These results underscore the unexpected diversity of pathways to resistance and the importance of continued surveillance for novel resistance mutations.

Data availability

Sequencing data have been deposited in the NCBI SRA database under accession number PRJNA540288.

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

Article and author information

Author details

  1. Samantha G Palace

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7849-8078
  2. Yi Wang

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Daniel H F Rubin

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael A Welsh

    Department of Microbiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8268-6285
  5. Tatum D Mortimer

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kevin Cole

    Public Health England, Royal Sussex County Hospital, Brighton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. David W Eyre

    Big Data Institute, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Suzanne Walker

    Department of Microbiology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Yonatan H Grad

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    For correspondence
    ygrad@hsph.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5646-1314

Funding

Richard and Susan Smith Family Foundation

  • Yonatan H Grad

National Institutes of Health (R01 AI132606)

  • Yonatan H Grad

National Institutes of Health (R01 GM76710)

  • Suzanne Walker

National Institutes of Health (F32 GM123579)

  • Michael A Welsh

National Institutes of Health (T32 GM007753)

  • Daniel H F Rubin

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

Reviewing Editor

  1. Christina L Stallings, Washington University School of Medicine, United States

Version history

  1. Received: August 27, 2019
  2. Accepted: February 1, 2020
  3. Accepted Manuscript published: February 3, 2020 (version 1)
  4. Version of Record published: February 11, 2020 (version 2)

Copyright

© 2020, Palace 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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  1. Samantha G Palace
  2. Yi Wang
  3. Daniel H F Rubin
  4. Michael A Welsh
  5. Tatum D Mortimer
  6. Kevin Cole
  7. David W Eyre
  8. Suzanne Walker
  9. Yonatan H Grad
(2020)
RNA polymerase mutations cause cephalosporin resistance in clinical Neisseria gonorrhoeae isolates
eLife 9:e51407.
https://doi.org/10.7554/eLife.51407

Share this article

https://doi.org/10.7554/eLife.51407

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