title: Fluconazole downregulates metallothionein expression and increases copper cytotoxicity in Microsporum canis.
abstract: Azole antifungals are widely used to treat infections with dermatophyte fungi. Whereas it is well established that this class of drugs interferes with fungal ergosterol synthesis, little is known about its potential other biological effects. Here we report the isolation and structural organization of Microsporum canis metallothionein gene and demonstrate that fluconazole is able to downregulate the baseline as well as copper-induced expression of this gene. Since this effect occurred within 30 min after exposure of the fungus to fluconazole, it is unlikely that it is due to impaired ergosterol synthesis. Our additional demonstration that fluconazole enhances copper toxicity for M. canis suggests that inhibition of metallothionein expression by fluconazole is biologically relevant and may represent an important additional mode of the antifungal action of this drug. Therefore our data indicate that antifungal effects of azole derivatives might not only be due to interference with cell wall synthesis but may also affect other biological circuits within the fungal cells.
authors.affiliation: Ludwig Boltzmann Institute for venero-dermatological infection, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090, Vienna, Austria.
authors.forename: Aumaid
authors.initials: A
authors.lastname: Uthman
authors.forename: Sassan
authors.initials: S
authors.lastname: Rezaie
authors.forename: Michael
authors.initials: M
authors.lastname: Dockal
authors.forename: Jozef
authors.initials: J
authors.lastname: Ban
authors.forename: Josef
authors.initials: J
authors.lastname: Söltz-Szöts
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D003300:Copper / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004357:Drug Synergism; D015725:Fluconazole / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D008864:Microsporum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D016415:Sequence Alignment
chemical_list: D000935:Antifungal Agents; D012333:RNA, Messenger; D003300:Copper; D015725:Fluconazole; D008668:Metallothionein