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Polymyxin B lethality requires energy-dependent outer membrane disruption

Carolina Borrelli1,2,3,4, Edward J A Douglas1,2, Sophia M A Riley1,2

  • 1Centre for Bacterial Resistance Biology, Imperial College London, London, UK.

Nature Microbiology
|September 29, 2025
PubMed

Insights

Metabolic activity is crucial for polymyxin B (PmB) antibiotic effectiveness against bacteria like Escherichia coli. Stationary-phase bacteria become tolerant unless metabolically active, revealing a key factor in antibiotic tolerance.

Area of Science:

  • Microbiology
  • Antibiotic Resistance
  • Bacterial Physiology

Background:

  • Polymyxin antibiotics, including polymyxin B (PmB), target lipopolysaccharides (LPSs) in bacterial membranes.
  • The precise mechanism of bacterial killing by polymyxins remains incompletely understood.

Purpose of the Study:

  • To investigate the role of metabolic activity in polymyxin B lethality.
  • To elucidate the mode of action of polymyxin B in Escherichia coli.

Main Methods:

  • Utilized atomic force microscopy to observe bacterial surface changes.
  • Assessed LPS loss from the outer membrane.
  • Investigated the impact of metabolic state (exponential vs. stationary phase) and nutrient availability on antibiotic efficacy.
  • Examined the effect of the MCR-1 resistance determinant.

Main Results:

  • Polymyxin B lethality against Escherichia coli is dependent on bacterial metabolic activity.
  • Stationary-phase bacteria exhibited tolerance to PmB unless a carbon source was provided.
  • Antibiotic treatment induced outer membrane disruptions and LPS loss, requiring LPS synthesis and transport.
  • The MCR-1 resistance determinant blocked PmB-mediated LPS loss.
  • Outer membrane disruption facilitated PmB entry to the inner membrane, causing cell death via energy-independent permeabilization.

Conclusions:

  • Metabolic activity is essential for polymyxin B's lethal effects.
  • Metabolic inactivity confers tolerance to polymyxin antibiotics.
  • Understanding this mechanism can inform strategies against polymyxin-resistant bacteria.

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