Laboratory of Pathology of Infectious Diseases (LIM50), Department of Pathology, Medical School of Sao Paulo University, Av. Dr. Arnaldo, 455. Cerqueira Cesar, Sao Paulo, 01246-903, SP, Brazil.
Sao Paulo State University (UNESP), Institute of Biosciences, Sao Vicente, Praca Infante Dom Henrique, s/n, 11330-900 Sao Vicente, SP, Brazil.
Curr Top Med Chem. 2018;18(27):2338-2346. doi: 10.2174/1568026619666181220114627.
Leishmaniasis is an infectious disease caused by protozoal parasites belonging to Leishmania genus. Different clinical outcomes can be observed depending on the parasite species and health condition of patients. It can range from single cutaneous lesion until deadly visceral form. The treatment of all forms of leishmaniasis is based on pentavalent antimonials, and in some cases, the second-line drug, amphotericin B is used. Beside the toxicity of both drugs, parasites can be resistant to antimonial in some areas of the world. This makes fundamental the characterization of new drugs with leishmanicidal effect. Thus, the aim of the present work was to study the leishmanicidal activity of drugs able to interfere with ergosterol pathway (fenticonazole, tioconazole, nystatin, rosuvastatin and voriconazole) against promastigote and amastigote forms of L.(L.) amazonensis, L.(V.) braziliensis and L.(L.) infantum, and its impact on morphological and physiological changes in L.(L.) amazonensis or in host macrophages. We observed that fenticonazole, tioconazole and nystatin drugs eliminated promastigote and intracellular amastigotes, being fenticonazole and nystatin the most selective towards amastigote forms. Rosuvastatin and voriconazole did not present activity against amastigote forms of Leishmania sp. In addition, the drugs with leishmanicidal activity interfered with parasite mitochondrion. Although drugs did not stimulate NO and H2O2, specially fenticonazole was able to alkalize infected host macrophages. These results suggest well established and non-toxic antifungal drugs can be repurposed and used in leishmaniasis.
利什曼病是一种由原生动物寄生虫引起的传染病，属于利什曼属。根据寄生虫种类和患者健康状况的不同，可能会出现不同的临床结果。它可以从单个皮肤损伤到致命的内脏形式。所有形式的利什曼病的治疗都基于五价锑，在某些情况下，使用二线药物两性霉素 B。除了这两种药物的毒性外，寄生虫在世界上的某些地区可能对锑产生耐药性。这使得具有杀利什曼原虫作用的新药的特征成为必要。因此，本工作的目的是研究能够干扰麦角固醇途径的药物（芬替康唑、酮康唑、制霉菌素、罗苏伐他汀和伏立康唑）对前鞭毛体和无鞭毛体形式的 L.(L.) amazonensis、L.(V.) braziliensis 和 L.(L.) infantum 的杀利什曼原虫活性及其对 L.(L.) amazonensis 或宿主巨噬细胞形态和生理变化的影响。我们观察到芬替康唑、酮康唑和制霉菌素药物消除了前鞭毛体和细胞内无鞭毛体，芬替康唑和制霉菌素对无鞭毛体形式最具选择性。罗苏伐他汀和伏立康唑对利什曼属的无鞭毛体形式没有活性。此外，具有杀利什曼原虫活性的药物干扰了寄生虫线粒体。尽管这些药物没有刺激 NO 和 H2O2 的产生，特别是芬替康唑能够使感染的宿主巨噬细胞碱化。这些结果表明，已确立且无毒的抗真菌药物可以被重新利用并用于利什曼病。
