A Genomewide Screen in Schizosaccharomyces pombe for Genes Affecting the Sensitivity of Antifungal Drugs That Target Ergosterol

We performed a genomewide screen for altered sensitivity to antifungal drugs, including clotrimazole and terbinafine, that tar-get 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 11mutants 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, ribo-some biosynthesis and assembly, regulation of transcription and translation, cell wall organization and biogenesis, mitochon-drion 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. Further-more, the 109 sensitive mutants were tested for sensitivity to micafungin, another antifungal drug that inhibits (1,3)--D-glucan synthase, and 57 hypersensitive mutants were identified, suggesting that these mutants were defective in cell wall integrity. Alto-gether, our findings in fission yeast have shed light onmolecular pathways associated with the cellular response to ergosterol biosynthesis inhibitors andmay provide useful information for developing strategies aimed at sensitizing cells to these drugs. Fungal diseases, especially opportunistic fungal infections, haveincreased dramatically over the past 2 decades as a result of th