Mandala S M, Thornton R A, Rosenbach M, Milligan J, Garcia-Calvo M, Bull H G, Kurtz M B
Department of Biochemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
J Biol Chem. 1997 Dec 19;272(51):32709-14. doi: 10.1074/jbc.272.51.32709.
In the course of screening for antifungal agents we have discovered a novel compound isolated from an endophytic fungus that inhibits fungal sphingolipid synthesis. Khafrefungin, which is composed of aldonic acid linked via an ester to a C22 modified alkyl chain, has fungicidal activity against Candida albicans, Cryptococcus neoformans, and Saccharomyces cerevisiae. Sphingolipid synthesis is inhibited in these organisms at the step in which phosphoinositol is transferred to ceramide, resulting in accumulation of ceramide and loss of all of the complex sphingolipids. In vitro, khafrefungin inhibits the inositol phosphoceramide synthase of C. albicans with an IC50 of 0.6 nM. Khafrefungin does not inhibit the synthesis of mammalian sphingolipids thus making this the first reported compound that is specific for the fungal pathway.
在筛选抗真菌剂的过程中，我们发现了一种从内生真菌中分离出的新型化合物，它能抑制真菌鞘脂的合成。哈夫瑞芬净由通过酯键连接到C22修饰烷基链上的醛糖酸组成，对白色念珠菌、新型隐球菌和酿酒酵母具有杀菌活性。在这些生物体中，鞘脂合成在磷酸肌醇转移到神经酰胺的步骤中受到抑制，导致神经酰胺积累以及所有复杂鞘脂的丧失。在体外，哈夫瑞芬净以0.6 nM的IC50抑制白色念珠菌的肌醇磷酸神经酰胺合酶。哈夫瑞芬净不抑制哺乳动物鞘脂的合成，因此这是首个报道的对真菌途径具有特异性的化合物。
