title: Neutron diffraction studies of the interaction between amphotericin B and lipid-sterol model membranes.
abstract: Over the last 50 years or so, amphotericin has been widely employed in treating life-threatening systemic fungal infections. Its usefulness in the clinic, however, has always been circumscribed by its dose-limiting side-effects, and it is also now compromised by an increasing incidence of pathogen resistance. Combating these problems through development of new anti-fungal agents requires detailed knowledge of the drug's molecular mechanism, but unfortunately this is far from clear. Neutron diffraction studies of the drug's incorporation within lipid-sterol membranes have here been performed to shed light on this problem. The drug is shown to disturb the structures of both fungal and mammalian membranes, and co-localises with the membrane sterols in a manner consistent with trans-membrane pore formation. The differences seen in the membrane lipid ordering and in the distributions of the drug-ergosterol and drug-cholesterol complexes within the membranes are consistent with the drug's selectivity for fungal vs. human cells.
authors.affiliation: Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Foglia
authors.forename: M Jayne
authors.initials: MJ
authors.lastname: Lawrence
authors.forename: Bruno
authors.initials: B
authors.lastname: Demeė
authors.forename: Giovanna
authors.initials: G
authors.lastname: Fragneto
authors.forename: David
authors.initials: D
authors.lastname: Barlow
mesh_terms: D000666:Amphotericin B / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D004875:Ergosterol / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008563:Membrane Lipids / Q000737:chemistry*; D033363:Neutron Diffraction; D013261:Sterols / Q000737:chemistry
chemical_list: D008055:Lipids; D008563:Membrane Lipids; D013261:Sterols; D000666:Amphotericin B; D002784:Cholesterol; D004875:Ergosterol