title: Comparison of D0870, a new triazole antifungal agent, to fluconazole for inhibition of Candida albicans cytochrome P-450 by using in vitro assays.
abstract: D0870 was 12 to 15 times more active than fluconazole in experiments to determine the MIC for growth arrest for two isolates of Candida albicans. A biochemical comparison of in vitro sterol biosynthesis in cell extracts showed only a twofold superiority of D0870 over fluconazole. A large differentiation (10-fold) in 50% saturating concentrations obtained by examining the binding of the azoles to microsomal P-450 was observed in a type II binding spectrophotometric assay, possibly reflecting the differential affinity for more than one P-450 enzyme. Additional mechanisms besides affinity for the target enzyme sterol 14 alpha-demethylase, such as differential intracellular accumulation of drug, may contribute to the differences in antifungal activity.
authors.affiliation: Department of Molecular Biology and Biotechnology, Krebs Institute for Biomolecular Research, Sheffield University, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Venkateswarlu
authors.forename: D W
authors.initials: DW
authors.lastname: Denning
authors.forename: N J
authors.initials: NJ
authors.lastname: Manning
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004875:Ergosterol / Q000096:biosynthesis; D015725:Fluconazole / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008826:Microbial Sensitivity Tests; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D014230:Triazoles; C058219:ICI 195739; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D004875:Ergosterol