RUI: The Three Facets of Amphotericin B Activity

RUI：两性霉素 B 活性的三个方面

• 批准号: 0135268
• 负责人: Scott Hartsel
• 金额: $ 23.5万
• 依托单位: University of Wisconsin-Eau Claire
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0135268&HistoricalAwards=false
• 关键词: RUI; Three; Facets; Amphotericin; Activity

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.

目前市场上有三种膜活性抗生素两性霉素B(Amb)的脂质相关超分子制剂：AmBisome、两性霉素和Abelcet。它们在物理上是根本不同的：AmBisome是真正的封闭式脂质体双层制剂，两性离子是带有硫酸胆固醇的胶束分散体，而Abelcet是交错的脂类分散体。尽管存在这些差异，但与哺乳动物细胞相比，这三种制剂都会破坏真菌膜，而且都比最初的胶束商业制剂(AMB：脱氧胆酸盐的摩尔比约为1：2(Fungizone，FZ))更具活性。简单的AMB或FZ溶液可以用中温(70℃，20分钟)处理，以产生AMB的新的自缔合状态，AMB是一种超聚集体，称为热处理真菌(HFZ)。该项目的目标是梳理这五种两性霉素B超分子制剂的特定生化和生物物理性质，使它们对真菌细胞膜和哺乳动物细胞膜具有选择性反应。影响AMB制剂毒性和选择性的三个因素将通过光谱和分子生物学方法进行研究：1)通过离子通道形成直接的膜活性，2)由于AMB复合体在血清脂蛋白/蛋白质存在时稳定性的不同而导致的分布和递送的差异，以及3)启动炎性细胞因子反应。