In vitro antileishmanial activity of ravuconazole, a triazole antifungal drug, as a potential treatment for leishmaniasis
In vitro antileishmanial activity of ravuconazole, a triazole antifungal drug, as a potential treatment for leishmaniasis
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DOI：
10.1093/jac/dky229
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发表时间：
2018-09-01
影响因子：
5.2
通讯作者：
Fernandes Rodrigues, Juliany Cola
中科院分区：
文献类型：
--
作者：
de Macedo Silva, Sara Teixeira;Visbal, Gonzalo;Fernandes Rodrigues, Juliany Cola
目的：利什曼病是由利什曼原虫属原虫引起的世界性疾病，是世界上最重要的被忽视的疾病之一。目前，利什曼病的病原学治疗效果不一，存在副作用严重、毒性大、费用高、耐药病例增多等问题。因此，迫切需要用于利什曼病的安全、口服和具有成本效益的药物。以前，我们的小组已经显示了麦角甾醇生物合成抑制剂对亚马逊利什曼原虫的影响。在此，我们显示了雷康唑对L。亚马逊河流域;方法：采用细胞培养、荧光显微镜、电子显微镜、高分辨毛细管气相色谱-质谱联用、荧光分析法和流式细胞术等方法，对雷唑康唑进行体外研究。结果表明，雷武康唑能抑制L.亚马逊前鞭毛体和细胞内无鞭毛体在体外，具有个位数至亚微摩尔的IC 50值，引起寄生虫的形态，超微结构，细胞活力和生理学的几个改变。的线粒体是显着影响的治疗，导致线粒体跨膜电位的崩溃，从而导致抑制ATP的生产，结合活性氧和线粒体超氧化物的生产增加;通过透射电子显微镜，细胞器显示出完全改变的超微结构。治疗改变了血脂谱，表现出深刻的14-去甲基内源性固醇pool.Conclusions耗尽：这些结果表明，雷康唑可能是治疗利什曼病的替代选择。
Objectives: Leishmaniasis, one of the most significant neglected diseases around the world, is caused by protozoan parasites of the Leishmania genus. Nowadays, the available aetiological treatments for leishmaniasis have variable effectiveness and several problems such as serious side effects, toxicity, high cost and an increasing number of resistance cases. Thus, there is an urgent need for safe, oral and cost-effective drugs for leishmaniases. Previously, our group has shown the effect of the ergosterol biosynthesis inhibitors on Leishmania amazonensis. Herein, we showed the effect of ravuconazole against L. amazonensis; ravuconazole is a second-generation triazole antifungal drug that has good bioavailability after oral administration and a long terminal half-life in humans, a broad activity spectrum, high effectiveness in treatment of mycosis and negligible side effects.Methods: Several methodologies were used: cell culture, fluorescence and electron microscopy, high-resolution capillary GC coupled with MS, fluorimetry and flow cytometry.Results: Our results showed that ravuconazole was able to inhibit the proliferation of L. amazonensis promastigotes and intracellular amastigotes in vitro, with single-digit to sub-micromolar IC50 values, causing several alterations in the morphology, ultrastructure, cell viability and physiology of the parasites. The mitochondrion was significantly affected by the treatment, resulting in a collapse of the mitochondrial transmembrane potential that consequently led to inhibition of ATP production, combined with an increase in reactive oxygen species and mitochondrial superoxide production; by transmission electron microscopy, the organelle displayed a completely altered ultrastructure. The treatment changed the lipid profile, showing a profound depletion of the 14-desmethyl endogenous sterol pool.Conclusions: These results suggest that ravuconazole could be an alternative option for the treatment of leishmaniasis.