title: Prothioconazole and prothioconazole-desthio activities against Candida albicans sterol 14-α-demethylase.
abstract: Prothioconazole is a new triazolinthione fungicide used in agriculture. We have used Candida albicans CYP51 (CaCYP51) to investigate the in vitro activity of prothioconazole and to consider the use of such compounds in the medical arena. Treatment of C. albicans cells with prothioconazole, prothioconazole-desthio, and voriconazole resulted in CYP51 inhibition, as evidenced by the accumulation of 14α-methylated sterol substrates (lanosterol and eburicol) and the depletion of ergosterol. We then compared the inhibitor binding properties of prothioconazole, prothioconazole-desthio, and voriconazole with CaCYP51. We observed that prothioconazole-desthio and voriconazole bind noncompetitively to CaCYP51 in the expected manner of azole antifungals (with type II inhibitors binding to heme as the sixth ligand), while prothioconazole binds competitively and does not exhibit classic inhibitor binding spectra. Inhibition of CaCYP51 activity in a cell-free assay demonstrated that prothioconazole-desthio is active, whereas prothioconazole does not inhibit CYP51 activity. Extracts from C. albicans grown in the presence of prothioconazole were found to contain prothioconazole-desthio. We conclude that the antifungal action of prothioconazole can be attributed to prothioconazole-desthio.
authors.affiliation: College of Medicine, Swansea University, Swansea, Wales, UK.
authors.forename: Josie E
authors.initials: JE
authors.lastname: Parker
authors.forename: Andrew G S
authors.initials: AG
authors.lastname: Warrilow
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Cools
authors.forename: Bart A
authors.initials: BA
authors.lastname: Fraaije
authors.forename: John A
authors.initials: JA
authors.lastname: Lucas
authors.forename: Katarina
authors.initials: K
authors.lastname: Rigdova
authors.forename: William J
authors.initials: WJ
authors.lastname: Griffiths
authors.forename: Diane E
authors.initials: DE
authors.lastname: Kelly
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D058886:Sterol 14-Demethylase / Q000378:metabolism*; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C550005:prothioconazole; D058886:Sterol 14-Demethylase; D065819:Voriconazole