Neutron diffraction studies of the interaction between amphotericin B and lipid-sterol model membranes

TY - JOUR

T1 - Neutron diffraction studies of the interaction between amphotericin B and lipid-sterol model membranes

AU - Foglia, Fabrizia

AU - Lawrence, M. Jayne

AU - Deme, Bruno

AU - Fragneto, Giovanna

AU - Barlow, David

PY - 2012/10/29

Y1 - 2012/10/29

N2 - 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.

AB - 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.

U2 - 10.1038/srep00778

DO - 10.1038/srep00778

M3 - Article

SN - 2045-2322

VL - 2

JO - Scientific Reports

JF - Scientific Reports

M1 - 778

ER -