Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids
Broad-spectrum antifungal activities and mechanism of drimane sesquiterpenoids
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DOI：
10.15698/mic2020.06.719
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发表时间：
2020-06-01
期刊：
影响因子：
4.6
通讯作者：
Vediyappan, Govindsamy
中科院分区：
文献类型：
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作者：
Edouarzin, Edruce;Horn, Connor;Vediyappan, Govindsamy
以(+)-马兜铃内酯为原料，合成了(-)-德里曼醇和(+)-白念珠醇等8个倍半萜类化合物，并对它们的抗真菌活性进行了评价。3个化合物，(-)-德里门诺、(+)-白念珠醇和(1R，2R，4aS，8aS)-2-hydroxy-2，5，5，8a-tetramethyl-decahydronaphthalene-1-carbaldehyde(4)对白色念珠菌有很强的抑制活性。(-)-曲霉烯醇是三者中最强的抑制剂(浓度为8-µg/ml，可使各种真菌100%死亡)，不仅对白色念珠菌具有杀菌作用，而且对其他真菌如曲霉、隐球菌、肺孢子菌、芽孢子菌、萨克森氏菌和对氟康唑耐药的白色念珠菌、光滑念珠菌、克鲁斯念珠菌、近缘念珠菌和金黄色念珠菌也有抑制作用。这些观察结果表明，德里梅诺是一种广谱抗真菌药物。高浓度(100微克/毫升)的地尔蒙可引起真菌细胞壁/膜的破裂。在白色念珠菌感染的线虫模型中，德里门诺从白色念珠菌介导的死亡中拯救了蠕虫，表明德里门诺在后生动物中是可以耐受的和具有生物活性的。对酿酒酵母(非必需纯合子和必需杂合子)和白色念珠菌(Tn插入突变体)收集的全基因组适合性分析显示了可能的基因和受地尔米诺影响的途径。通过白念珠菌突变斑点分析，Crk1激酶相关基因产物Ret2、CDC37和orf19.759、orf19.1672和orf19.4382被发现与德里门诺的作用机制有关。本研究中发现的三个ORF都是新发现的，似乎与Crk1功能相关。此外，计算模拟结果表明，为了提高抗真菌活性，可能对包括A环在内的德里梅诺的结构进行了修改。
Eight drimane sesquiterpenoids including (-)-drimenol and (+)-albicanol were synthesized from (+)-sclareolide and evaluated for their anti-fungal activities. Three compounds, (-)-drimenol, (+)-albicanol, and (1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalene-1-carbaldehyde (4) showed strong activity against C. albicans. (-)-Drimenol, the strongest inhibitor of the three, (at concentrations of 8 - 64 mu g/ml, causing 100% death of various fungi), acts not only against C. albicans in a fungicidal manner, but also inhibits other fungi such as Aspergillus, Cryptococcus, Pneumocystis, Blastomyces, Saksenaea and fluconazole resistant strains of C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. auris. These observations suggest that drimenol is a broad-spectrum antifungal agent. At a high concentration (100 mu g/ml) drimenol caused rupture of the fungal cell wall/membrane. In a nematode model of C. albicans infection, drimenol rescued the worms from C. albicans-mediated death, indicating drimenol is tolerable and bioactive in metazoans. Genome-wide fitness profiling assays of both S. cerevisiae (nonessential homozygous and essential heterozygous) and C. albicans (Tn-insertion mutants) collections revealed putative genes and pathways affected by drimenol. Using a C. albicans mutant spot assay, the Crk1 kinase associated gene products, Ret2, Cdc37, and orf19.759, orf19.1672, and orf19.4382 were revealed to be involved in drimenol's mechanism of action. The three orfs identified in this study are novel and appear to be linked with Crk1 function. Further, computational modeling results suggest possible modifications of the structure of drimenol, including the A ring, for improving the antifungal activity.