title: A genomewide screen in Schizosaccharomyces pombe for genes affecting the sensitivity of antifungal drugs that target ergosterol biosynthesis.
abstract: We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that target ergosterol biosynthesis using a Schizosaccharomyces pombe gene deletion library consisting of 3,004 nonessential haploid deletion mutants. We identified 109 mutants that were hypersensitive and 11 mutants that were resistant to these antifungals. Proteins whose absence rendered cells sensitive to these antifungals were classified into various functional categories, including ergosterol biosynthesis, membrane trafficking, histone acetylation and deacetylation, ubiquitination, signal transduction, ribosome biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochondrion function, amino acid metabolism, nucleic acid metabolism, lipid metabolism, meiosis, and other functions. Also, proteins whose absence rendered cells resistant to these antifungals were classified into functional categories including mitochondrion function, ubiquitination, membrane trafficking, cell polarity, chromatin remodeling, and some unknown functions. Furthermore, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)-β-D-glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Altogether, our findings in fission yeast have shed light on molecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors and may provide useful information for developing strategies aimed at sensitizing cells to these drugs.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, China Medical University, Shenyang, China. fangyue@mail.cmu.edu.cn
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.forename: Lingling
authors.initials: L
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Wurentuya
authors.initials: W
authors.lastname: Jaiseng
authors.forename: Ben
authors.initials: B
authors.lastname: Zhang
authors.forename: Tomonori
authors.initials: T
authors.lastname: Takami
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kuno
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects; D002480:Cellulase / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003022:Clotrimazole / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000235:genetics*; D004875:Ergosterol / Q000096:biosynthesis* / Q000235:genetics*; D017353:Gene Deletion; D005816:Genetic Complementation Test; D055106:Genome-Wide Association Study; D006657:Histones / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009281:Naphthalenes / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000077291:Terbinafine; D054875:Ubiquitination / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D006657:Histones; D009281:Naphthalenes; D002480:Cellulase; D003022:Clotrimazole; D000077291:Terbinafine; D004875:Ergosterol