SQ109 inhibits proliferation of Leishmania donovani by disruption of intracellular Ca2+ homeostasis, collapsing the mitochondrial electrochemical potential (Δψm) and affecting acidocalcisomes
SQ109 inhibits proliferation of Leishmania donovani by disruption of intracellular Ca2+ homeostasis, collapsing the mitochondrial electrochemical potential (Δψm) and affecting acidocalcisomes
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DOI：
10.1007/s00436-019-06560-y
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发表时间：
2020-01-02
影响因子：
2
通讯作者：
Benaim, Gustavo
中科院分区：
文献类型：
--
作者：
Gil, Zain;Martinez-Sotillo, Nathalia;Benaim, Gustavo
杜氏利什曼原虫是内脏利什曼病的病原体。每年有 5 亿新感染病例报告，主要发生在贫困社区，这降低了制药行业的兴趣。因此，重新定位新药是对抗这些寄生虫的理想策略。 SQ109 是一种处于 IIb/III 期临床试验的化合物，用于治疗耐药结核分枝杆菌，对导致恰加斯病的克氏锥虫和皮肤和粘膜皮肤利什曼病的病原体墨西哥利什曼原虫具有有效作用。在后者中，针对巨噬细胞内无鞭毛体的毒性剂量非常低（IC50 类似于 11 nM）。所提出的对墨西哥 L. mexicana 的作用机制涉及通过线粒体电化学势 (Delta psi(m)) 的崩溃来破坏寄生虫细胞内 Ca2+ 稳态。在目前的工作中，我们展示了 SQ109 对杜诺瓦尼利什曼病（内脏利什曼病是这些感染的更严重且独特致命形式）的寄生虫的有效作用，对巨噬细胞内无鞭毛体的毒性作用甚至低于在墨西哥利什曼病中获得的毒性作用（IC50 为 7.17 +/- 0.09 nM），并且选择性指数 > 800，甚至高于在利什曼病中获得的毒性作用。墨西哥。我们还首次证明，SQ109 除了破坏寄生虫的 Delta psi(m) 之外，还能对寄生虫酸钙体、参与生物能学和许多其他重要功能（包括 Ca2+ 稳态）的重要细胞器造成非常快速的损害。药物对这些细胞器的两种作用都会导致细胞内 Ca2+ 浓度急剧增加，从而导致寄生虫死亡。
Leishmania donovani is the causative agent of visceral leishmaniasis. Annually, 500 million new cases of infection are reported mainly in poor communities, decreasing the interest of the pharmaceutical industries. Therefore, the repositioning of new drugs is an ideal strategy to fight against these parasites. SQ109, a compound in phase IIb/III of clinical trials to treat resistant Mycobacterium tuberculosis, has a potent effect against Trypanosoma cruzi, responsible for Chagas' disease, and on Leishmania mexicana, the causative agent of cutaneous and muco-cutaneous leishmaniasis. In the latter, the toxic dose against intramacrophagic amastigotes is very low (IC50 similar to 11 nM). The proposed mechanism of action on L. mexicana involves the disruption of the parasite intracellular Ca2+ homeostasis through the collapse of the mitochondrial electrochemical potential (Delta psi(m)). In the present work, we show a potent effect of SQ109 on L. donovani, the parasite responsible for visceral leishmaniasis, the more severe and uniquely lethal form of these infections, obtaining a toxic effect on amastigotes inside macrophages even lower to that obtained in L. mexicana (IC50 of 7.17 +/- 0.09 nM) and with a selectivity index > 800, even higher than in L. mexicana. We also demonstrated for first time that SQ109, besides collapsing Delta psi(m) of the parasite, induced a very rapid damage to the parasite acidocalcisomes, essential organelles involved in the bioenergetics and many other important functions, including Ca2+ homeostasis. Both effects of the drug on these organelles generated a dramatic increase in the intracellular Ca2+ concentration, causing parasite death.