Ludewig G, Williams J M, Li Y, Staben C
T. H. Morgan School of Biological Sciences, University of Kentucky, Lexington 40506-0225.
Antimicrob Agents Chemother. 1994 May;38(5):1123-8. doi: 10.1128/AAC.38.5.1123.
We used Saccharomyces cerevisiae as a model system in which to examine the mechanism of action of the anti-Pneumocystis drug pentamidine. Pentamidine at low concentrations inhibited S. cerevisiae growth on nonfermentable carbon sources (50% inhibitory concentration [IC50] of 1.25 micrograms/ml in glycerol). Pentamidine inhibited growth on fermentable energy sources only at much higher concentrations (IC50 of 250 micrograms/ml in glucose). Inhibition at low pentamidine concentrations in glycerol was due to cytostatic activity rather than cytotoxic or mutagenic activity. Pentamidine also rapidly inhibited respiration by intact yeast cells, although inhibitory concentrations were much higher than those inhibitory to growth (IC50 of 100 micrograms/ml for respiration). Pentamidine also induced petite mutations, although only at concentrations much higher than those required for growth inhibition. These results suggest that a function essential for respiratory growth is inhibited by pentamidine and that pentamidine affects mitochondrial processes. We propose the hypothesis that the primary cellular target of pentamidine in S. cerevisiae is the mitochondrion.
我们使用酿酒酵母作为模型系统来研究抗肺孢子菌药物喷他脒的作用机制。低浓度的喷他脒抑制酿酒酵母在非发酵碳源上的生长（在甘油中50%抑制浓度[IC50]为1.25微克/毫升）。喷他脒仅在高得多的浓度下才抑制可发酵能源上的生长（在葡萄糖中IC50为250微克/毫升）。在甘油中低浓度喷他脒的抑制作用是由于细胞生长抑制活性，而非细胞毒性或诱变活性。喷他脒还能迅速抑制完整酵母细胞的呼吸作用，尽管抑制浓度远高于抑制生长的浓度（呼吸作用的IC50为100微克/毫升）。喷他脒也会诱导小菌落突变，尽管仅在远高于生长抑制所需的浓度下才会出现。这些结果表明，喷他脒抑制了呼吸生长所必需的一种功能，并且喷他脒影响线粒体过程。我们提出假说，即喷他脒在酿酒酵母中的主要细胞靶点是线粒体。
