Callyspongiolide is a marine-derived macrolide that kills cells in a caspase-independent manner. NCI COMPARE analysis of human tumor cell line toxicity data for synthetic callyspongiolide indicated that its pattern of cytotoxicity correlated with that seen for concanamycin A, an inhibitor of the vacuolar-type H⁺-ATPase (V-ATPase). Using yeast as a model system, we report that treatment with synthetic callyspongiolide phenocopied a loss of V-ATPase activity including (1) inability to grow on a nonfermentable carbon source, (2) rescue of cell growth via supplementation with Fe²⁺, (3) pH-sensitive growth, and (4) a vacuolar acidification defect visualized using the fluorescent dye quinacrine. Crucially, in an in vitro assay, callyspongiolide was found to dose-dependently inhibit yeast V-ATPase (IC₅₀ = 10 nM). Together, these data identify callyspongiolide as a new and highly potent V-ATPase inhibitor. Notably, callyspongiolide is the first V-ATPase inhibitor known to be expelled by Pdr5p.

中文翻译：

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Callyspongiolide 是液泡 ATP 酶的有效抑制剂

Callyspongiolide 是一种海洋衍生的大环内酯类化合物，以不依赖半胱天冬酶的方式杀死细胞。NCI 对合成海藻内酯的人肿瘤细胞系毒性数据进行的比较分析表明，其细胞毒性模式与刀豆霉素 A（一种液泡型 H ⁺ -ATP 酶 (V-ATPase)抑制剂）的细胞毒性模式相关。使用酵母作为模型系统，我们报告说，用合成海藻内酯处理会导致 V-ATPase 活性的丧失，包括（1）无法在不可发酵的碳源上生长，（2）通过补充 Fe ²⁺来挽救细胞生长，（ 3) pH 敏感生长，和 (4) 使用荧光染料奎纳克林可视化的液泡酸化缺陷。至关重要的是，在体外测定，发现海藻内酯以剂量依赖性方式抑制酵母 V-ATP 酶 (IC ₅₀ = 10 nM)。总之，这些数据将 calyspongiolide 鉴定为一种新的高效 V-ATPase 抑制剂。值得注意的是，callyspongiolide 是第一个已知被 Pdr5p 排出的 V-ATPase 抑制剂。