title: Profiling of the effects of antifungal agents on yeast cells based on morphometric analysis.
abstract: 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.
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Abraham Abera
authors.initials: AA
authors.lastname: Gebre
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Cholgwang
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Karen
authors.initials: K
authors.lastname: Kubo
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohnuki
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, 277-8561, Japan ohya@k.u-tokyo.ac.jp.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohya
mesh_terms: D000935:Antifungal Agents / Q000145:classification / Q000494:pharmacology*; D002473:Cell Wall / Q000187:drug effects; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics*; D004875:Ergosterol / Q000037:antagonists & inhibitors; D008826:Microbial Sensitivity Tests; D009696:Nucleic Acids / Q000096:biosynthesis / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
chemical_list: D000935:Antifungal Agents; D009696:Nucleic Acids; D025262:Vacuolar Proton-Translocating ATPases; D004875:Ergosterol
keywords: CalMorph; antifungal agent; cell wall; mode of action; morphological profiling; systematic classifier; target prediction