Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil ; Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem, Rio de Janeiro, Brazil.
Instituto Venezolano de Investigaciones Científicas, Centro de Bioquímica y Biofísica, Caracas, Venezuela.
PLoS One. 2013 Dec 23;8(12):e83247. doi: 10.1371/journal.pone.0083247. eCollection 2013.
Leishmaniasis, caused by protozoan parasites of the Leishmania genus, is one of the most prevalent neglected tropical diseases. It is endemic in 98 countries, causing considerable morbidity and mortality. Pentavalent antimonials are the first line of treatment for leishmaniasis except in India. In resistant cases, miltefosine, amphotericin B and pentamidine are used. These treatments are unsatisfactory due to toxicity, limited efficacy, high cost and difficult administration. Thus, there is an urgent need to develop drugs that are efficacious, safe, and more accessible to patients. Trypanosomatids, including Leishmania spp. and Trypanosoma cruzi, have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. Inhibition of ergosterol biosynthesis is increasingly recognized as a promising target for the development of new chemotherapeutic agents. The aim of this work was to investigate the antiproliferative, physiological and ultrastructural effects against Leishmania amazonensis of itraconazole (ITZ) and posaconazole (POSA), two azole antifungal agents that inhibit sterol C14α-demethylase (CYP51). Antiproliferative studies demonstrated potent activity of POSA and ITZ: for promastigotes, the IC50 values were 2.74 µM and 0.44 µM for POSA and ITZ, respectively, and for intracellular amastigotes, the corresponding values were 1.63 µM and 0.08 µM, for both stages after 72 h of treatment. Physiological studies revealed that both inhibitors induced a collapse of the mitochondrial membrane potential (ΔΨm), which was consistent with ultrastructural alterations in the mitochondrion. Intense mitochondrial swelling, disorganization and rupture of mitochondrial membranes were observed by transmission electron microscopy. In addition, accumulation of lipid bodies, appearance of autophagosome-like structures and alterations in the kinetoplast were also observed. In conclusion, our results indicate that ITZ and POSA are potent inhibitors of L. amazonensis and suggest that these drugs could represent novel therapies for the treatment of leishmaniasis, either alone or in combination with other agents.
利什曼病是由利什曼原虫属的原生动物寄生虫引起的，是最流行的被忽视的热带病之一。它在 98 个国家流行，导致相当高的发病率和死亡率。除印度外，五价锑剂是利什曼病的一线治疗药物。在耐药病例中，米替福新、两性霉素 B 和喷他脒被使用。这些治疗方法因毒性、疗效有限、成本高和给药困难而不理想。因此，迫切需要开发有效、安全且更易于患者获得的药物。原生动物门生物，包括利什曼原虫属和克氏锥虫，对麦角固醇和其他 24-烷基固醇有基本需求，而哺乳动物细胞中不存在这些固醇。抑制麦角固醇生物合成越来越被认为是开发新化疗药物的有前途的目标。本工作的目的是研究伊曲康唑（ITZ）和泊沙康唑（POSA）对亚马逊利什曼原虫的增殖、生理和超微结构的影响，这两种唑类抗真菌药物抑制甾醇 C14α-去甲基酶（CYP51）。增殖研究表明 POSA 和 ITZ 具有很强的活性：对于前鞭毛体，POSA 和 ITZ 的 IC50 值分别为 2.74 μM 和 0.44 μM，对于内阿米巴原虫，相应的值分别为 1.63 μM 和 0.08 μM，均为治疗后 72 小时的两个阶段。生理研究表明，两种抑制剂均诱导线粒体膜电位（ΔΨm）崩溃，这与线粒体的超微结构改变一致。透射电子显微镜观察到线粒体强烈肿胀、线粒体膜结构紊乱和破裂。此外，还观察到脂质体积累、自噬体样结构出现和动基体改变。总之，我们的结果表明 ITZ 和 POSA 是亚马逊利什曼原虫的有效抑制剂，并表明这些药物可能代表治疗利什曼病的新疗法，无论是单独使用还是与其他药物联合使用。
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