Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane
Akshay Sabnis,
Katheryn LH Hagart,
Anna Klöckner,
Michele Becce,
Lindsay E Evans,
R Christopher D Furniss,
Despoina AI Mavridou,
Ronan Murphy,
Molly M Stevens,
Jane C Davies,
Gérald J Larrouy-Maumus,
Thomas B Clarke,
Andrew M Edwards
Affiliations
Akshay Sabnis
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
Katheryn LH Hagart
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
Anna Klöckner
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom; Department of Bioengineering, Imperial College London, London, United Kingdom; Department of Materials, Imperial College London, London, United Kingdom; Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
Michele Becce
Department of Bioengineering, Imperial College London, London, United Kingdom; Department of Materials, Imperial College London, London, United Kingdom; Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
Lindsay E Evans
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom; Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, London, United Kingdom
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
Despoina AI Mavridou
Department of Molecular Biosciences, University of Texas at Austin, Austin, United States
Ronan Murphy
National Heart and Lung Institute, Imperial College London, London, United Kingdom; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom
Department of Bioengineering, Imperial College London, London, United Kingdom; Department of Materials, Imperial College London, London, United Kingdom; Institute of Biomedical Engineering, Imperial College London, London, United Kingdom
Jane C Davies
National Heart and Lung Institute, Imperial College London, London, United Kingdom; Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, United Kingdom
Gérald J Larrouy-Maumus
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
Thomas B Clarke
MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom
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 Escherichia coli 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 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.
