Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum
Identification of an Aminothiazole with Antifungal Activity against Intracellular Histoplasma capsulatum
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DOI：
10.1128/aac.00459-13
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Rappleye, Chad A.
中科院分区：
文献类型：
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作者：
Edwards, Jessica A.;Kemski, Megan M.;Rappleye, Chad A.
作为真核生物，真菌具有相对较少的分子，这些分子与哺乳动物细胞组分相比足够独特以用作药物靶标。因此，大多数目前的抗真菌剂具有显著的宿主细胞毒性。主要真菌病原体（例如，组织胞浆菌）是特别值得关注的，因为很少有抗真菌药能有效治疗它们。为了确定用于治疗组织胞浆菌病的其他抗真菌候选药物，我们开发了一种用于监测组织胞浆菌生长的高通量平台，并将其用于3，600种市售化合物的表型筛选。鉴定了七种抑制组织胞浆菌酵母生长的命中化合物。化合物41 F5在微摩尔浓度下对组织胞浆菌酵母具有抑真菌活性，50%抑制浓度（IC 50）为0.87 μ M，并且相对于宿主细胞对酵母具有最大的选择性（至少62倍）。在结构上，41 F5由氨基噻唑核心组成，在2-位具有脂环族取代基，在5-位具有芳香族取代基。41 F5抑制液体培养物中的组织胞浆菌生长，并类似地抑制巨噬细胞内的酵母细胞，巨噬细胞是这种真菌病原体在感染期间的实际宿主环境。重要的是，41 F5保护受感染的宿主细胞免受组织胞浆菌诱导的巨噬细胞死亡，使这种氨基噻唑命中化合物成为开发作为组织胞浆菌感染的抗真菌剂的优秀候选者。
As eukaryotes, fungi possess relatively few molecules sufficiently unique from mammalian cell components to be used as drug targets. Consequently, most current antifungals have significant host cell toxicity. Primary fungal pathogens (e.g., Histoplasma) are of particular concern, as few antifungals are effective in treating them. To identify additional antifungal candidates for the treatment of histoplasmosis, we developed a high-throughput platform for monitoring Histoplasma growth and employed it in a phenotypic screen of 3,600 commercially available compounds. Seven hit compounds that inhibited Histoplasma yeast growth were identified. Compound 41F5 has fungistatic activity against Histoplasma yeast at micromolar concentrations, with a 50% inhibitory concentration (IC50) of 0.87 mu M, and has the greatest selectivity for yeast (at least 62-fold) relative to host cells. Structurally, 41F5 consists of an aminothiazole core with an alicyclic substituent at the 2-position and an aromatic substituent at the 5-position. 41F5 inhibits Histoplasma growth in liquid culture and similarly inhibits yeast cells within macrophages, the actual host environment of this fungal pathogen during infection. Importantly, 41F5 protects infected host cells from Histoplasma-induced macrophage death, making this aminothiazole hit compound an excellent candidate for development as an antifungal for Histoplasma infections.