Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
- Imperial College London, United Kingdom
- University of Texas at Austin, United States
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
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Data from: Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membraneDryad Digital Repository, doi: 10.5061/dryad.98sf7m0hh.
Article and author information
Author details
R Christopher D Furniss
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
- 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
- Received: December 16, 2020
- Accepted: March 31, 2021
- Accepted Manuscript published: April 6, 2021 (version 1)
- 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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Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
eLife 10:e65836.
https://doi.org/10.7554/eLife.65836
Further reading
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