Characterization of an allosteric inhibitor of fungal-specific C-24 sterol methyltransferase to treat Candida albicans infections
Characterization of an allosteric inhibitor of fungal-specific C-24 sterol methyltransferase to treat Candida albicans infections
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DOI：
10.1016/j.chembiol.2023.04.010
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发表时间：
2023-05-18
影响因子：
8.6
通讯作者：
Lou，Hongxiang
中科院分区：
文献类型：
--
作者：
Jin，Xueyang;Hou，Xuben;Lou，Hongxiang
丝状菌是致病真菌白念珠菌的重要毒力因子。通过干扰甾醇合成抑制白念珠菌菌丝体的形成是开发安全性高的抗真菌药物的重要思路。在这里，我们使用表达绿色荧光蛋白标记的Dpp 3的白色念珠菌菌株进行高通量筛选，以通过干扰麦角固醇合成来鉴定抗菌丝剂。安替比林衍生物H55的特征在于具有最小的细胞毒性和在多种培养条件下对白色念珠菌菌丝形成的有效抑制。H55单一疗法在唑类耐药念珠菌病的小鼠模型中表现出治疗功效。H55处理增加了C-24甾醇甲基转移酶（Erg 6）的底物酵母甾醇的积累。酶分析，光亲和标记，分子模拟，诱变和细胞热位移测定的结果支持H55作为Erg 6的变构抑制剂。总的来说，H55，真菌特异性酶Erg 6的抑制剂，具有治疗白色念珠菌感染的潜力。
Filamentation is an important virulence factor of the pathogenic fungusCandida albicans. The abolition ofCandida albicanshyphal formation by disrupting sterol synthesis is an important concept for the development of antifungal drugs with high safety. Here, we conduct a high-throughput screen using aC.albicansstrain expressing green fluorescent protein-labeled Dpp3 to identify anti-hypha agents by interfering with ergosterol synthesis. The antipyrine derivative H55 is characterized to have minimal cytotoxicity and potent inhibition ofC.albicanshyphal formation in multiple cultural conditions. H55 monotherapy exhibits therapeutic efficacy in mouse models of azole-resistant candidiasis. H55 treatment increases the accumulation of zymosterol, the substrate of C-24 sterol methyltransferase (Erg6). The results of enzyme assays, photoaffinity labeling, molecular simulation, mutagenesis, and cellular thermal shift assays support H55 as an allosteric inhibitor of Erg6. Collectively, H55, an inhibitor of the fungal-specific enzyme Erg6, holds potential to treatC.albicansinfections.