Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

  1. R Christopher D Furniss
  2. Nikol Kaderabkova
  3. Declan Barker
  4. Patricia Bernal
  5. Evgenia Maslova
  6. Amanda AA Antwi
  7. Helen E McNeil
  8. Hannah L Pugh
  9. Laurent Dortet
  10. Jessica MA Blair
  11. Gerald J Larrouy-Maumus
  12. Ronan R McCarthy
  13. Diego Gonzalez
  14. Despoina AI Mavridou  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. The University of Texas at Austin, United States
  3. Universidad de Sevilla, Spain
  4. Brunel University London, United Kingdom
  5. University of Birmingham, United Kingdom
  6. Paris-Sud University, France
  7. University of Neuchatel, Switzerland

Abstract

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

Data availability

All data generated during this study that support the findings are included in the manuscript or in the Supplementary Information.

Article and author information

Author details

  1. R Christopher D Furniss

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Nikol Kaderabkova

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Declan Barker

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Patricia Bernal

    Department of Microbiology, Universidad de Sevilla, Seville, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6228-0496
  5. Evgenia Maslova

    Department of Life Sciences, Brunel University London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Amanda AA Antwi

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Helen E McNeil

    Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Hannah L Pugh

    Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Laurent Dortet

    Department of Bacteriology-Hygiene, Paris-Sud University, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Jessica MA Blair

    Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6904-4253
  11. Gerald J Larrouy-Maumus

    Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Ronan R McCarthy

    Department of Life Sciences, Brunel University London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Diego Gonzalez

    Department of Biology, University of Neuchatel, Neuchatel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  14. Despoina AI Mavridou

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    For correspondence
    despoina.mavridou@austin.utexas.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7449-1151

Funding

Medical Research Council (MR/M009505/1)

  • Despoina AI Mavridou

Swiss National Science Foundation (PZ00P3_180142)

  • Diego Gonzalez

Academy of Medical Sciences (SBF006\1040)

  • Ronan R McCarthy

National Institutes of Health (R01AI158753)

  • Despoina AI Mavridou

Biotechnology and Biological Sciences Research Council (BB/M02623X/1)

  • Jessica MA Blair

Wellcome Trust (105603/Z/14/Z)

  • Gerald J Larrouy-Maumus

British Society for Antimicrobial Chemotherapy (BSAC-2018-0095)

  • Ronan R McCarthy

Biotechnology and Biological Sciences Research Council (BB/V007823/1)

  • Ronan R McCarthy

Swiss National Science Foundation (P300PA_167703)

  • Diego Gonzalez

NC3Rs (NC/V001582/1)

  • Ronan R McCarthy

Biotechnology and Biological Sciences Research Council (BB/M011178/1)

  • Nikol Kaderabkova

Biotechnology and Biological Sciences Research Council (BB/M01116X/1)

  • Hannah L Pugh

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

Reviewing Editor

  1. Melanie Blokesch, Ecole Polytechnique Fédérale de Lausanne, Switzerland

Version history

  1. Received: May 19, 2020
  2. Preprint posted: August 28, 2021 (view preprint)
  3. Accepted: January 11, 2022
  4. Accepted Manuscript published: January 13, 2022 (version 1)
  5. Version of Record published: February 22, 2022 (version 2)

Copyright

© 2022, Furniss 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. R Christopher D Furniss
  2. Nikol Kaderabkova
  3. Declan Barker
  4. Patricia Bernal
  5. Evgenia Maslova
  6. Amanda AA Antwi
  7. Helen E McNeil
  8. Hannah L Pugh
  9. Laurent Dortet
  10. Jessica MA Blair
  11. Gerald J Larrouy-Maumus
  12. Ronan R McCarthy
  13. Diego Gonzalez
  14. Despoina AI Mavridou
(2022)
Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding
eLife 11:e57974.
https://doi.org/10.7554/eLife.57974

Share this article

https://doi.org/10.7554/eLife.57974

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