Cryptococcal meningitis is a prevalent invasive fungal infection that causes around 180 000 deaths annually. Currently, treatment for cryptococcal meningitis is limited and new therapeutic options are needed. Historically, medicinal plants are used to treat infectious and inflammatory skin infections. Tryptanthrin is a natural product commonly found in these plants. In this study, we demonstrated that tryptanthrin had antifungal activity with minimum inhibitory concentration (MIC) of 2 μg/ml against Cryptococcus species and of 8 μg/ml against Trichophyton rubrum. Further analysis demonstrated that tryptanthrin exerted fungistatic and potent antifungal activity at elevated temperature. In addition, tryptanthrin exhibited a synergistic effect with the calcineurin inhibitors FK506 and cyclosporine A against Cryptococcus neoformans. Furthermore, our data showed that tryptanthrin induced cell cycle arrest at the G₁/S phase by regulating the expression of genes encoding cyclins and the SBF/MBF complex (CLN1, MBS1, PCL1, and WHI5) in C. neoformans. Screening of a C. neoformans mutant library further revealed that tryptanthrin was associated with various transporters and signaling pathways such as the calcium transporter (Pmc1) and protein kinase A signaling pathway. In conclusion, tryptanthrin exerted novel antifungal activity against Cryptococcus species through a mechanism that interferes with the cell cycle and signaling pathways.

中文翻译：

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天然生物碱色胺酮表现出新型抗隐球菌活性。


隐球菌性脑膜炎是一种流行的侵袭性真菌感染，每年导致约 18 万人死亡。目前，隐球菌性脑膜炎的治疗方法有限，需要新的治疗选择。从历史上看，药用植物被用来治疗传染性和炎症性皮肤感染。色胺酮是这些植物中常见的天然产物。在这项研究中，我们证明了色胺酮具有抗真菌活性，对隐球菌的最低抑菌浓度 (MIC) 为 2 μg/ml，对红色毛癣菌的最低抑菌浓度 (MIC) 为 8 μg/ml。进一步的分析表明，色胺酮在高温下发挥抑制真菌和有效的抗真菌活性。此外，色胺酮与钙调磷酸酶抑制剂FK506和环孢菌素A对新型隐球菌具有协同作用。此外，我们的数据表明，在新型隐球菌中，色胺酮通过调节编码细胞周期蛋白和SBF/MBF复合物（ CLN1、MBS1、PCL1和WHI5 ）的基因的表达，诱导细胞周期停滞在G ₁ /S期。对新型隐球菌突变体库的筛选进一步表明，色胺酮与多种转运蛋白和信号通路有关，例如钙转运蛋白（Pmc1）和蛋白激酶A信号通路。总之，色胺酮通过干扰细胞周期和信号传导途径的机制对隐球菌发挥新的抗真菌活性。