Electron Microscopy Unit, Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Lucknow, 226 031, India.
Academy of Scientific and Innovative Research, Chennai, 600113, India.
Apoptosis. 2018 Aug;23(7-8):420-435. doi: 10.1007/s10495-018-1468-5.
Natamycin, a Food and Drug Administration approved anti-fungal drug, and also used as a food additive was evaluated for anti-leishmanial activity since it is known to specifically bind to ergosterol, which is essential to these parasites but absent in mammals. Promising anti-proliferative activity was observed in both promastigote and amastigote forms of the parasite with IC values of 15 and 8 µM respectively and a selective index of 12.5. The ultrastructural effects of natamycin on both forms of the parasite and physiological effects on promastigotes were studied in detail for the first time. Electron microscopic observations in treated cells revealed sub-cellular changes like plasma membrane alterations, accumulation of vesicles in the flagellar pocket and extensive mitochondrial damage. Natamycin treatment in promastigotes resulted in elevation of cytosolic calcium (Ca) levels which caused irreversible loss of mitochondrial membrane potential. This resulted in depletion of cellular ATP levels along with ROS generation finally leading to apoptosis-like and necrotic cell death. In view of our observations along with the safety profile of an existing anti-fungal drug, natamycin may be further investigated for repurposing it as a promising drug candidate against Leishmaniasis.
纳他霉素是一种经美国食品和药物管理局批准的抗真菌药物，也被用作食品添加剂。由于其已知的特异性结合麦角固醇的特性，麦角固醇是这些寄生虫所必需的，但在哺乳动物中不存在，因此对其抗利什曼原虫活性进行了评估。在寄生虫的前鞭毛体和无鞭毛体形式中均观察到了有前途的抗增殖活性，IC 值分别为 15 和 8 µM，选择性指数为 12.5。这是首次详细研究纳他霉素对这两种寄生虫形式的超微结构作用和对前鞭毛体的生理作用。在处理过的细胞中的电子显微镜观察显示出亚细胞变化，如质膜改变、鞭毛囊中囊泡的积累和广泛的线粒体损伤。纳他霉素处理前鞭毛体导致细胞溶质钙离子 (Ca) 水平升高，从而导致线粒体膜电位不可逆转丧失。这导致细胞 ATP 水平耗尽以及 ROS 生成，最终导致类似凋亡和坏死的细胞死亡。鉴于我们的观察结果以及现有抗真菌药物的安全性概况，纳他霉素可能会进一步被研究作为一种有前途的抗利什曼病候选药物进行重新利用。
