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Membrane Cholesterol Reduces Polymyxin B Nephrotoxicity in Renal Membrane Analogs

Adree Khondker1, Richard J Alsop1, Alexander Dhaliwal1

  • 1Department of Physics and Astronomy, McMaster University, Hamilton, Ontario, Canada.

Biophysical Journal
|November 9, 2017
PubMed

Insights

Polymyxin B causes kidney damage by disrupting cell membranes. Cholesterol helps protect kidney membranes from this antibiotic, reducing damage and water permeation.

Area of Science:

  • Membrane biophysics
  • Antibiotic toxicology
  • Renal pharmacology

Background:

  • Polymyxin B (PmB) is a last-resort antibiotic with significant nephrotoxicity.
  • The precise molecular mechanisms underlying PmB-induced kidney damage remain unclear.

Purpose of the Study:

  • To elucidate the molecular basis of Polymyxin B nephrotoxicity.
  • To investigate the role of membrane cholesterol in modulating PmB-induced kidney membrane damage.

Main Methods:

  • Preparation of cholesterol-depleted and cholesterol-enriched kidney membrane analogs.
  • X-ray diffraction, molecular dynamics simulations, and electrochemistry to analyze membrane structure and peptide interactions.
  • Assessment of membrane damage and water permeation.

Main Results:

  • Polymyxin B induced membrane damage in both cholesterol-depleted and enriched membrane analogs.
  • Two populations of PmB were identified: membrane-associated and inserted peptides.
  • Cholesterol-rich membranes showed significantly reduced damage, decreased peptide clustering, and lower water permeation.
  • Cholesterol stabilized membrane structure and reduced lipid and peptide mobility, mitigating PmB's detrimental effects.

Conclusions:

  • Polymyxin B causes kidney membrane damage through peptide aggregation and increased water permeability.
  • Membrane cholesterol plays a protective role by stabilizing the bilayer and reducing PmB-induced structural instabilities and water influx.
  • Understanding these interactions could inform strategies to mitigate Polymyxin B nephrotoxicity.

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