Abstract

Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than outer membrane. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane. We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the cytoplasmic membrane of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.

Data availability

Source data for all figures has been deposited at Dryad: https://doi.org/10.5061/dryad.98sf7m0hh

The following data sets were generated

Article and author information

Author details

  1. Akshay Sabnis

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Katheryn L H Hagart

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Anna Klöckner

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Michele Becce

    Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Lindsay E Evans

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. R Christopher D Furniss

    Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5806-5099
  7. Despoina A I Mavridou

    Department of Molecular Biosciences, University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ronan Murphy

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Molly M Stevens

    Department of Materials, Department of Bioengineering, Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7335-266X
  10. Jane C Davies

    National Heart and Lung Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Gérald J Larrouy-Maumus

    MRC Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Thomas B Clarke

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  13. Andrew M Edwards

    MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
    For correspondence
    a.edwards@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7173-7355

Funding

Medical Research Council (PhD Studentship)

  • Akshay Sabnis

Wellcome Trust

  • Andrew M Edwards

NIHR Imperial Biomedical Research Centre

  • Andrew M Edwards

DFG

  • Anna Klöckner

Horizon 2020

  • Anna Klöckner

Rosetrees Trust

  • Molly M Stevens

Cystic Fibrosis Trust

  • Jane C Davies

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

Reviewing Editor

  1. Philip A Cole, Harvard Medical School, United States

Ethics

Animal experimentation: The use of mice was performed under the authority of the UK Home Office outlined in the Animals (Scientific Procedures) Act 1986 after ethical review by Imperial College London Animal Welfare and Ethical Review Body (PPL 70/7969).

Version history

  1. Received: December 16, 2020
  2. Accepted: March 31, 2021
  3. Accepted Manuscript published: April 6, 2021 (version 1)
  4. Version of Record published: May 4, 2021 (version 2)

Copyright

© 2021, Sabnis 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. Akshay Sabnis
  2. Katheryn L H Hagart
  3. Anna Klöckner
  4. Michele Becce
  5. Lindsay E Evans
  6. R Christopher D Furniss
  7. Despoina A I Mavridou
  8. Ronan Murphy
  9. Molly M Stevens
  10. Jane C Davies
  11. Gérald J Larrouy-Maumus
  12. Thomas B Clarke
  13. Andrew M Edwards
(2021)
Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
eLife 10:e65836.
https://doi.org/10.7554/eLife.65836

Share this article

https://doi.org/10.7554/eLife.65836

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