<br>人类寄生虫阴道毛滴虫天然产物抑制剂高通量、高内涵筛选系统的设计与应用。,ACS Infectious Diseases

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人类寄生虫阴道毛滴虫天然产物抑制剂高通量、高内涵筛选系统的设计与应用。
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-07-02 , DOI: 10.1021/acsinfecdis.9b00156
Jarrod B King ₁ , Adam C Carter ₁ , Wentao Dai ₁ , Jin Woo Lee ₁ , Yun-Seo Kil ₁ , Lin Du ₁ , Sara K Helff ₁ , Shengxin Cai ₁ , Brandt C Huddle ₁ , Robert H Cichewicz ₁

Affiliation

据估计，阴道毛滴虫影响着世界上惊人的 3.9% 人口，虽然许多感染者没有症状，但疾病的进展可能导致严重的健康问题。目前，硝基咪唑类药物是美国唯一批准用于治疗滴虫病的药物类别，这使得耐药性的传播成为现实问题。我们开发了一种新的基于图像的高通量、高内涵测定法，用于测试天然产物（纯化的化合物和提取物）的抗毛滴虫活性。将此检测系统应用于真菌天然产物提取物库，鉴定出三类天然产物抑制剂，它们对阴道毛滴虫表现出中度至强的活性：蒽醌、呫吨酮-蒽醌异二聚体和十氢萘连接的特特拉姆酸。含有代谢物。四酸盐天然产物成为最有前途的候选分子，吡咯菌素 A (51) 对寄生虫表现出有效的活性 (EC50 = 60 nM)，但该代谢物对哺乳动物细胞系的毒性有限（与 3T3 相比，选择性指数值为 100 和 167）分别为成纤维细胞和 Ect1 正常宫颈细胞）。基于成像的测定系统是一种强大的工具，用于从复杂的天然产物混合物中以生物测定为指导纯化单组分抗毛滴虫生物分子。

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Design and Application of a High-Throughput, High-Content Screening System for Natural Product Inhibitors of the Human Parasite Trichomonas vaginalis.

It is estimated that Trichomonas vaginalis affects an astonishing 3.9% of the world's population, and while many of those infected are asymptomatic, progression of the disease can lead to serious health problems. Currently, the nitroimidazoles constitute the only drug class approved to treat trichomoniasis in the United States, which makes the spread of drug resistance a realistic concern. We developed a new image-based, high-throughput, and high-content assay for testing natural products (purified compounds and extracts) for antitrichomonal activity. Applying this assay system to a library of fungal natural product extracts led to the identification of three general classes of natural product inhibitors that exhibited moderate to strong activities against T. vaginalis: anthraquinones, xanthone-anthraquinone heterodimers, and decalin-linked tetramic-acid-containing metabolites. The tetramate natural products emerged as the most promising candidate molecules with pyrrolocin A (51) exhibiting potent activity against the parasite (EC50 = 60 nM), yet this metabolite showed limited toxicity to mammalian cell lines (selectivity index values of 100 and 167 versus 3T3 fibroblast and Ect1 normal cervical cells, respectively). The imaging-based assay system is a powerful tool for the bioassay-guided purification of single-component antitrichomonal biomolecules from complex natural product mixtures.

更新日期：2019-06-20

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