1. Microbiology and Infectious Disease
Download icon

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
Research Article
  • Cited 3
  • Views 1,104
  • Annotations
Cite this article as: eLife 2020;9:e51407 doi: 10.7554/eLife.51407

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.

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

Publication 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.

Metrics

  • 1,104
    Page views
  • 182
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Ecology
    2. Microbiology and Infectious Disease
    Elizabeth A Landis et al.
    Research Article

    Humans have relied on sourdough starter microbial communities to make leavened bread for thousands of years, but only a small fraction of global sourdough biodiversity has been characterized. Working with a community-scientist network of bread bakers, we determined the microbial diversity of 500 sourdough starters from four continents. In sharp contrast with widespread assumptions, we found little evidence for biogeographic patterns in starter communities. Strong co-occurrence patterns observed in situ and recreated in vitro demonstrate that microbial interactions shape sourdough community structure. Variation in dough rise rates and aromas were largely explained by acetic acid bacteria, a mostly overlooked group of sourdough microbes. Our study reveals the extent of microbial diversity in an ancient fermented food across diverse cultural and geographic backgrounds.

    1. Microbiology and Infectious Disease
    Elsio A Wunder et al.
    Research Article

    Leptospirosis is the leading zoonotic disease in terms of morbidity and mortality worldwide. Effective prevention is urgently needed as the drivers of disease transmission continue to intensify. The key challenge has been developing a widely applicable vaccine that protects against the >300 serovars that can cause leptospirosis. Live attenuated mutants are enticing vaccine candidates and poorly explored in the field. We evaluated a recently characterized motility-deficient mutant lacking the expression of a flagellar protein, FcpA. Although the fcpA- mutant has lost its ability to cause disease, transient bacteremia was observed. In two animal models, immunization with a single dose of the fcpA- mutant was sufficient to induce a robust anti-protein antibodies response that promoted protection against infection with different pathogenic Leptospira species. Furthermore, characterization of the immune response identified a small repertoire of biologically relevant proteins that are highly conserved among pathogenic Leptospira species and potential correlates of cross-protective immunity.