A qnr-plasmid allows aminoglycosides to induce SOS in Escherichia coli

  1. Anamaria Babosan
  2. David Skurnik
  3. Anaëlle Muggeo
  4. Gerald Pier
  5. Zeynep Baharoglu
  6. Thomas Jové
  7. Marie-Cécile Ploy
  8. Sophie Griveau
  9. Fethi Bedioui
  10. Sébastien Vergnolle
  11. Sophie Moussalih
  12. Christophe de Champs
  13. Didier Mazel
  14. Thomas Guillard  Is a corresponding author
  1. Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, France
  2. Inserm U1151-Equipe 11, Université Paris Descartes, France
  3. Brigham and Women's Hospital, United States
  4. Institut Pasteur, France
  5. Université de Limoges, Inserm, France
  6. PSL Research University, CNRS, France
  7. Centre Hospitalier de Troyes, France

Abstract

The plasmid-mediated quinolone resistance (PMQR) genes have been shown to promote high-level bacterial resistance to fluoroquinolone antibiotics, potentially leading to clinical treatment failures. In Escherichia coli, sub-minimum inhibitory concentrations (sub-MICs) of the widely used fluoroquinolones are known to induce the SOS response. Interestingly, the expression of several PMQR qnr genes is controlled by the SOS master regulator, LexA. During the characterization of a small qnrD-plasmid carried in E. coli, we observed that the aminoglycosides become able to induce the SOS response in this species, thus leading to the elevated transcription of qnrD. Our findings show that induction of the SOS response is due to nitric oxide (NO) accumulation in presence of sub-MIC of aminoglycosides. We demonstrated that the NO accumulation is driven by two plasmid genes, ORF3 and ORF4, whose products act at two levels. ORF3 encodes a putative flavin adenine dinucleotide (FAD)-binding oxidoreductase which helps NO synthesis, while ORF4 codes for a putative fumarate and nitrate reductase (FNR)-type transcription factor, related to an O2-responsive regulator of hmp expression, able to repress the Hmp-mediated NO detoxification pathway of E. coli. Thus, this discovery, that other major classes of antibiotics may induce the SOS response could have worthwhile implications for antibiotic stewardship efforts in preventing the emergence of resistance.

Data availability

Source data are provided as a Source Data file. Flow cytometry data have been deposited in FlowRepository as FR-FCM-Z3MR repository ID (http://flowrepository.org/id/RvFrzhOtiB4Hrd9yMMTEF2gAckZvYVa365phD9U0fVTabQb7ibCDqV8Gzbgb02dm).

Article and author information

Author details

  1. Anamaria Babosan

    Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France
    Competing interests
    The authors declare that no competing interests exist.
  2. David Skurnik

    Institut Necker-Enfants Malades, Inserm U1151-Equipe 11, Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Anaëlle Muggeo

    Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Gerald Pier

    Department of Medicine, Brigham and Women's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9112-2331
  5. Zeynep Baharoglu

    Unité Plasticité du Génome Bactérien, CNRS UMR3525, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3477-2685
  6. Thomas Jové

    CHU Limoges, RESINFIT, UMR 1092, Université de Limoges, Inserm, Limoges, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Marie-Cécile Ploy

    CHU Limoges, RESINFIT, UMR 1092, Université de Limoges, Inserm, Limoges, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Sophie Griveau

    Institute of Chemistry for Life and Health Sciences, PSL Research University, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Fethi Bedioui

    Institute of Chemistry for Life and Health Sciences, PSL Research University, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Sébastien Vergnolle

    Laboratoire d'Hématologie, Centre Hospitalier de Troyes, Troyes, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Sophie Moussalih

    Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Christophe de Champs

    Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Didier Mazel

    Unité Plasticité du Génome Bactérien, CNRS UMR3525, Institut Pasteur, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6482-6002
  14. Thomas Guillard

    Inserm UMR-S 1250 P3Cell, SFR CAP-Santé, Université de Reims-Champagne-Ardenne, Reims, France
    For correspondence
    tguillard@chu-reims.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3795-0398

Funding

Université de Reims Champagne-Ardenne

  • Anamaria Babosan
  • Christophe de Champs
  • Thomas Guillard

Conseil Regional de Champagne-Ardenne

  • Anamaria Babosan
  • Christophe de Champs
  • Thomas Guillard

Association pour le Developpement de la Microbiologie et de l'Immunologie Rémoises

  • Anamaria Babosan

International Union of Biochemistry and Molecular Biology

  • Anamaria Babosan

Agence Nationale de la Recherche (ANR-10-LABX-62- IBEID)

  • Didier Mazel

Centre National de la Recherche Scientifique

  • Zeynep Baharoglu
  • Didier Mazel

Institut Pasteur

  • Zeynep Baharoglu
  • Didier Mazel

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

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Version history

  1. Received: April 17, 2021
  2. Preprint posted: April 30, 2021 (view preprint)
  3. Accepted: January 12, 2022
  4. Accepted Manuscript published: January 17, 2022 (version 1)
  5. Version of Record published: January 25, 2022 (version 2)

Copyright

© 2022, Babosan 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. Anamaria Babosan
  2. David Skurnik
  3. Anaëlle Muggeo
  4. Gerald Pier
  5. Zeynep Baharoglu
  6. Thomas Jové
  7. Marie-Cécile Ploy
  8. Sophie Griveau
  9. Fethi Bedioui
  10. Sébastien Vergnolle
  11. Sophie Moussalih
  12. Christophe de Champs
  13. Didier Mazel
  14. Thomas Guillard
(2022)
A qnr-plasmid allows aminoglycosides to induce SOS in Escherichia coli
eLife 11:e69511.
https://doi.org/10.7554/eLife.69511

Share this article

https://doi.org/10.7554/eLife.69511

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