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Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane

Akshay Sabnis1, Katheryn Lh Hagart1, Anna Klöckner1,2,3,4

  • 1MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, United Kingdom.

Elife
|April 6, 2021
PubMed

Insights

Colistin resistance is rising. New research shows colistin kills bacteria by targeting lipopolysaccharide (LPS) in the cytoplasmic membrane, not the outer membrane. This discovery enables new therapeutic strategies against resistant bacteria.

Area of Science:

  • Microbiology
  • Pharmacology
  • Biochemistry

Background:

  • Colistin is a critical last-resort antibiotic with limitations in efficacy and increasing resistance.
  • The precise bactericidal mechanism of colistin, particularly its interaction with bacterial membranes, remained incompletely understood.
  • Lipopolysaccharide (LPS) modification, mediated by MCR-1, was identified as a key factor in colistin resistance.

Purpose of the Study:

  • To elucidate the exact mechanism by which colistin exerts its bactericidal activity.
  • To investigate the role of LPS localization in colistin resistance and susceptibility.
  • To develop novel therapeutic strategies for combating colistin-resistant bacterial infections.

Main Methods:

  • Investigated MCR-1 mediated colistin resistance in *Escherichia coli*, focusing on LPS modification.
  • Determined colistin's bactericidal action by analyzing its interaction with LPS in different cellular compartments (cytoplasmic membrane vs. outer membrane).
  • Utilized the LPS transport inhibitor murepavadin to induce LPS accumulation in *Pseudomonas aeruginosa*'s cytoplasmic membrane, followed by colistin treatment.

Main Results:

  • Discovered that MCR-1 mediated colistin resistance in *Escherichia coli* is linked to LPS modification in the cytoplasmic membrane, not the outer membrane.
  • Demonstrated that colistin's bactericidal effect stems from targeting LPS within the cytoplasmic membrane.
  • Showed that inhibiting LPS transport with murepavadin enhances *Pseudomonas aeruginosa*'s susceptibility to colistin in vitro and improves treatment efficacy in vivo.

Conclusions:

  • Colistin's primary bactericidal mechanism involves targeting lipopolysaccharide (LPS) in the cytoplasmic membrane.
  • LPS modification in the cytoplasmic membrane is crucial for MCR-1 mediated colistin resistance.
  • Combining LPS transport inhibition with colistin presents a promising therapeutic strategy to overcome colistin resistance and improve treatment outcomes.
Keywords:
ColistinE. coliPolymyxinPseudomonasinfectious diseaselipopolysaccharidemicrobiologyphospholipids

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