Gebre Abraham Abera, Okada Hiroki, Kim Cholgwang, Kubo Karen, Ohnuki Shinsuke, Ohya Yoshikazu
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan
FEMS Yeast Res. 2015 Aug;15(5):fov040. doi: 10.1093/femsyr/fov040. Epub 2015 Jun 10.
The incidence of fungal infection and evolution of multidrug resistance have increased the need for new antifungal agents. To gain further insight into the development of antifungal drugs, the phenotypic profiles of currently available antifungal agents of three classes-ergosterol, cell wall and nucleic acid biosynthesis inhibitors-were investigated using yeast morphology as a chemogenomic signature. The comparison of drug-induced morphological changes with the deletion of 4718 non-essential genes not only confirmed the mode of action of the drugs but also revealed an unexpected connection among ergosterol, vacuolar proton-transporting V-type ATPase and cell-wall-targeting drugs. To improve, simplify and accelerate drug development, we developed a systematic classifier that sorts a newly discovered compound into a class with a similar mode of action without any mutant information. Using well-characterized agents as target unknown compounds, this method successfully categorized these compounds into their respective classes. Based on our data, we suggest that morphological profiling can be used to develop novel antifungal drugs.
真菌感染的发生率和多重耐药性的演变增加了对新型抗真菌药物的需求。为了更深入地了解抗真菌药物的开发，利用酵母形态作为化学基因组学特征，研究了目前可用的三类抗真菌药物——麦角固醇、细胞壁和核酸生物合成抑制剂——的表型特征。将药物诱导的形态变化与4718个非必需基因的缺失进行比较，不仅证实了药物的作用模式，还揭示了麦角固醇、液泡质子转运V型ATP酶和细胞壁靶向药物之间意想不到的联系。为了改进、简化和加速药物开发，我们开发了一种系统分类器，无需任何突变信息就能将新发现的化合物分类到具有相似作用模式的类别中。使用特征明确的药物作为目标未知化合物，该方法成功地将这些化合物分类到各自的类别中。基于我们的数据，我们建议形态学分析可用于开发新型抗真菌药物。
