title: A genome-wide screening of potential target genes to enhance the antifungal activity of micafungin in Schizosaccharomyces pombe.
abstract: Micafungin is a non-reversible inhibitor of 1, 3-β-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. However, considering its relatively restricted antifungal spectrum, combination therapy with micafungin plus other agents should be considered in critically ill patients. To identify potential therapeutic targets for syncretic drug combinations that potentiate micafungin action, we carried out a genome-wide screen for altered sensitivity to micafungin by using the model yeast Schizosaccharomyces pombe mutant library. We confirmed that 159 deletion strains in the library are micafungin sensitive and classified them into various functional categories, including cell wall biosynthesis, gene expression and chromatin remodeling, membrane trafficking, signaling transduction, ubiquitination, ergosterol biosynthetic process and a variety of other known functions or still unknown functions. On the other hand, we also investigated the growth inhibitory activities of some well-known drugs in combination with micafungin including antifungal drug amphotericin B, fluconazole and immunosuppressive drug FK506. We found that amphotericin B in combination with micafungin showed a more potent inhibitory activity against wild-type cells than that of micafungin alone, whereas fluconazole in combination with micafungin did not. Also, the immunosuppressive drug FK506 showed synergistic inhibitory effect with micafungin on the growth of wild-type cells, whereas it decreased the inhibitory effect of micafungin in Δpmk1 cells, a deletion mutant of the cell wall integrity mitogen-activated protein kinase (MAPK) Pmk1. Altogether, our findings provide useful information for new potential drug combinations in the treatment of fungal infections.
authors.affiliation: Department of Oncology, the First Affiliated Hospital of Liaoning Medical University, Jinzhou, China. xinzhoulmu@gmail.com
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Yue
authors.initials: Y
authors.lastname: Fang
authors.forename: Wugan
authors.initials: W
authors.lastname: gerile
authors.forename: Wurentuya
authors.initials: W
authors.lastname: Jaiseng
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamada
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Kuno
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D054714:Echinocandins / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects / Q000235:genetics; D005800:Genes, Fungal / Q000235:genetics*; D023281:Genomics; D055666:Lipopeptides / Q000494:pharmacology*; D000077551:Micafungin; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D012568:Schizosaccharomyces / Q000166:cytology / Q000187:drug effects* / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D029702:Schizosaccharomyces pombe Proteins; D000666:Amphotericin B; D020928:Mitogen-Activated Protein Kinases; C516338:Pmk1 protein, S pombe; D000077551:Micafungin; D016559:Tacrolimus