Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
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- Akshay Sabnis
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Katheryn LH Hagart
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Anna Klöckner
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Michele Becce
- Department of Bioengineering, Imperial College London, London, United Kingdom
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- Lindsay E Evans
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- R Christopher D Furniss
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Despoina AI Mavridou
- Department of Molecular Biosciences, University of Texas at Austin, Austin, United States
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- Ronan Murphy
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
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- Molly M Stevens
- Department of Bioengineering, Imperial College London, London, United Kingdom
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- Jane C Davies
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
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- Gérald J Larrouy-Maumus
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Thomas B Clarke
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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- Andrew M Edwards
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
抄録
<jats:p>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 (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in <jats:italic>Escherichia coli</jats:italic> is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). 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 CM of <jats:italic>Pseudomonas aeruginosa</jats:italic>, 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.</jats:p>
収録刊行物
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- eLife
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eLife 10 2021-04-06
eLife Sciences Publications, Ltd