RUI: The Three Facets of Amphotericin B Activity

点击翻译按钮获取中文摘要

Three lipid-associated supramolecular preparations of the membrane-active antibiotic Amphotericin B (AmB) are currently on the market: AmBisome, Amphocil, and Abelcet. They are fundamentally different physically: AmBisome is a true closed liposomal bilayer preparation, Amphocil is micellar dispersion with cholesteryl sulfate and Abelcet is interdigitated lipid dispersion. Despite these differences, all three preparations damage fungal membranes compared to mammalian cell and all are more active than the original micellar commercial preparation consisting of AmB: deoxycholate in a mole ratio of ~1:2 (Fungizone, FZ). Simple AmB or FZ solutions may be treated with moderate heat (70 o C for 20 minutes) to produce a new self-associated state of AmB, a imsuperaggregatel., termed heat-treated Fungizone (HFZ). The goal of this project is to tease apart which specificbiochemical and biophysical properties of these five Amphotericin B supramolecular preparations make them selectively reactive toward fungal versus mammalian cell membranes. Three factors which influence the toxicity and selectivity of AmB preparations will be investigated by spectroscopic and molecular biology methods: 1) direct membrane activity via ion channel formation, 2) differences in distribution and delivery to tissues due to differences in stability of AmB complexes in the presence of serum lipoproteins/proteins, and 3) initiation of an inflammatory cytokine response.