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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen
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Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen

机译：从高通量筛选中鉴定出抗心力衰竭的新药领先药Corifungin

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Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.
机译：原发性阿米巴脑膜脑炎（PAM）是由自由生活的阿姆巴Naegleria fowleri引起的快速致死性感染。治疗PAM的首选药物是抗真菌抗生素两性霉素B，但其使用会带来严重的不良反应。此外，接受两性霉素B治疗的患者中很少有幸存的PAM。因此，迫切需要快速有效的药物来治疗PAM。为了促进对该病原体的药物筛选，开发了一种自动化的高通量筛选方法，并针对紧密相关的物种Naegleria gruberi进行了验证。在三个化合物库的初步筛选中鉴定出五种激酶抑制剂和NF-κB抑制剂。对于临床前药物开发渠道最重要的是，我们鉴定了corifungin，这是一种水溶性多烯大环内酯类药物，其对Naegleria的活性高于两性霉素B。用不同浓度的corifungin孵育的福氏猪滋养体的透射电子显微镜显示细胞质和质膜和线粒体的改变，然后完全溶解变形虫。对于每天一次的腹膜内剂量为9 mg / kg体重的每日一次，每天10 mg的腹膜内剂量，感染后17天大脑中不存在可检测的阿米巴，并且小鼠100％存活，从而证实了Corifungin在PAM小鼠模型中的体内功效。相同剂量的两性霉素B不会减少变形虫的生长，并且损害了小鼠的存活率。基于这些结果，美国FDA已经批准了可瑞芬净用于PAM的孤儿药地位。

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