Cryptococcus neoformans is one of the most important human fungal pathogens and causes life-threatening meningoencephalitis in immunocompromised patients. The current gold standard therapy for C. neoformans meningoencephalitis is based on medications that are over 50 years old and is not readily available in regions with high disease burden. Here, we report the mycologic, mechanistic, and pharmacologic characterization of a set of benzothioureas with highly selective fungicidal activity against C. neoformans. In addition, to direct antifungal activity, benzothioureas inhibit C. neoformans virulence traits. On the basis of a set of phenotypic, biochemical, and biophysical assays, the benzothioureas (BTUs) inhibit the late secretory pathway (post-Golgi), possibly through a direct interaction with Sav1, an orthologue of the Sec4-class small GTPase. Importantly, pharmacological characterization of the BTUs indicates it readily penetrates the blood-brain barrier. Together, our data support the further development of this scaffold as an antifungal agent with a novel mechanism of action against C. neoformans.

中文翻译：

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苯硫脲衍生物靶向人类真菌病原体新隐球菌的分泌途径。

新型隐球菌是人类最重要的真菌病原体之一，可在免疫功能低下的患者中引发威胁生命的脑膜脑炎。当前用于治疗新形成型梭菌脑膜脑炎的金标准疗法基于已有50多年历史的药物，并且在疾病负担高的地区尚不容易获得。在这里，我们报告了一组具有高选择性杀真菌活性的苯甲酸硫脲类的苯甲硫脲的真菌学，机理和药理学表征。另外，为了指导抗真菌活性，苯并硫脲抑制新孢子虫的毒力特性。根据一组表型，生化和生物物理分析，苯硫脲（BTU）可能通过与Sec4类小GTP酶的直向同源物Sav1直接相互作用来抑制晚期分泌途径（高尔基后）。重要的是，BTU的药理学特性表明它很容易穿透血脑屏障。总之，我们的数据支持该支架作为抗真菌剂的进一步开发，该支架具有针对新孢子虫的新型作用机制。