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Interactions of amphotericin B derivatives with lipid membranes--a molecular dynamics study

Jacek Czub1, Edward Borowski, Maciej Baginski

  • 1Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-952 Gdansk, Poland.

Biochimica Et Biophysica Acta
|July 31, 2007
PubMed

Insights

New Amphotericin B (AmB) derivatives, SAmE and PAmE, show improved fungal membrane targeting. Molecular dynamics reveal deeper penetration and distinct conformational changes, potentially reducing Amphotericin B toxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Amphotericin B (AmB) is a critical antifungal antibiotic.
  • AmB's toxicity stems from similar interactions with fungal and animal cell membranes.
  • Developing less toxic AmB derivatives with improved selectivity is crucial.

Purpose of the Study:

  • To analyze the interactions of novel Amphotericin B derivatives (SAmE, PAmE) with lipid membranes.
  • To compare the behavior of AmB and its derivatives in ergosterol- (fungal) and cholesterol- (animal) containing membranes.
  • To elucidate the molecular basis for potentially improved selectivity of SAmE and PAmE.

Main Methods:

  • Molecular dynamics simulations were employed.
  • Lipid bilayers containing either ergosterol or cholesterol were simulated.
  • Structural and dynamic properties of AmB and its derivatives within the membranes were analyzed.

Main Results:

  • AmB derivatives (SAmE, PAmE) penetrated the hydrophobic membrane region more deeply than AmB.
  • Modifications to AmB's amino and carboxyl groups induced conformational changes in the polar head.
  • AmB derivatives exhibited distinct wobbling dynamics based on the sterol type (ergosterol vs. cholesterol).

Conclusions:

  • Significant differences exist in how AmB and its derivatives interact with ergosterol- versus cholesterol-containing membranes.
  • These molecular differences, including penetration depth and conformational dynamics, likely underlie the observed enhanced selectivity of SAmE and PAmE.
  • The findings provide a molecular explanation for the reduced toxicity of the novel Amphotericin B derivatives.

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