Tani Kazunori, Usuki Yoshinosuke, Motoba Kazuhiko, Fujita Ken-ichi, Taniguchi Makoto
Graduate School of Science, Osaka City University, Japan.
J Antibiot (Tokyo). 2002 Mar;55(3):315-21. doi: 10.7164/antibiotics.55.315.
UK-2A is a potent antifungal antibiotic and its structure is highly similar to that of antimycin A3 (AA). UK-2A and AA inhibit mitochondrial electron transport at complex III. However, the antifungal activities of UK-2A and AA disappear after 48-hour treatment. In an attempt to improve the duration of the antifungal activity of UK-2A, several UK-2A derivatives were prepared by substituting its nine-membered dilactone ring with an n-alkyl or an isoprenyl moiety. Among all the derivatives tested, C9- and C10-UK-2A showed the most potent and durable antifungal activities against a strict aerobic yeast, Rhodotorula mucilaginosa IFO 0001. C9-UK-2A, in particular, continued to demonstrate its broad-spectrum antifungal activity after 120-hour treatment. Therefore, we focused on C9-UK-2A to further examine its mode of action against the yeast. Interestingly, C9-UK-2A did not inhibit cellular respiration of the cells even at concentrations greater than 100 microg/ml. C9-UK-2A gradually induced the efflux of potassium ions from the cells. Moreover, C9-UK-2A gradually induced the release of glucose from glucose-encapsulating liposomes. The patterns of efflux and release induced by C9-UK-2A were not as rapid as those seen with amphotericin B. These results suggest a membrane injury caused by C9-UK-2A in R. mucilaginosa IFO 0001.
UK - 2A是一种强效抗真菌抗生素，其结构与抗霉素A3（AA）高度相似。UK - 2A和AA在复合体III处抑制线粒体电子传递。然而，UK - 2A和AA的抗真菌活性在处理48小时后消失。为了延长UK - 2A的抗真菌活性持续时间，通过用正烷基或异戊二烯基部分取代其九元双内酯环制备了几种UK - 2A衍生物。在所有测试的衍生物中，C9 - 和C10 - UK - 2A对严格需氧酵母粘红酵母IFO 0001表现出最强和最持久的抗真菌活性。特别是C9 - UK - 2A在处理120小时后仍继续表现出其广谱抗真菌活性。因此，我们聚焦于C9 - UK - 2A以进一步研究其对酵母的作用方式。有趣的是，即使在浓度大于100微克/毫升时，C9 - UK - 2A也不抑制细胞的细胞呼吸。C9 - UK - 2A逐渐诱导细胞内钾离子外流。此外，C9 - UK - 2A逐渐诱导包封葡萄糖的脂质体释放葡萄糖。C9 - UK - 2A诱导的外流和释放模式不如两性霉素B所见的那样迅速。这些结果表明C9 - UK - 2A在粘红酵母IFO 0001中引起了膜损伤。
