title: Contribution of the Slt2-regulated transcription factors to echinocandin tolerance in Candida glabrata.
abstract: Echinocandin-class antifungals, including micafungin, are considered as the first-line treatment for Candida glabrata infections. However, recent epidemiological surveys have revealed an increasing number of C. glabrata isolates exhibiting decreased echinocandin susceptibilities. The Slt2 mitogen-activated protein kinase pathway is important for maintenance of cell wall integrity in fungi. Rlm1 and Swi4-Swi6 cell cycle box binding factor (SBF) are transcription factors downstream of Slt2. While Slt2 and Rlm1 play important roles in response to cell wall stresses, such as micafungin exposure, little is known about SBF in C. glabrata. Here, we generated C. glabrata strains lacking or overexpressing SWI4 and SWI6 and evaluated their susceptibilities to micafungin. Micafungin tolerance considerably decreased in the ∆swi4 strain, whereas it increased in the strains overexpressing SWI4. On the other hand, deletion of SWI6 slightly impaired micafungin tolerance, but overexpression of SWI6 had no effect. These results suggest that, although Swi4 and Swi6 form a protein complex, Swi4 is involved in micafungin tolerance more predominantly than Swi6 in C. glabrata. Furthermore, the overexpression of RLM1 induced increased micafungin tolerance in the wild-type background but not in the ∆swi4 and ∆swi6 strains, suggesting that Rlm1 and SBF function interdependently in response to micafungin exposure.
authors.affiliation: Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Nagayoshi
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Asuka
authors.initials: A
authors.lastname: Minematsu
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yamauchi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takazono
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Imamura
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kakeya
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D041221:Candida glabrata / Q000187:drug effects* / Q000235:genetics; D004361:Drug Tolerance; D054714:Echinocandins / Q000494:pharmacology*; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D055666:Lipopeptides / Q000494:pharmacology; D000077551:Micafungin; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D000077551:Micafungin
keywords: Candida glabrata; Swi4; Swi4-Swi6 cell cycle box binding factor; Swi6; cell wall integrity; echinocandin