title: Biochemical characterisation of ketoconazole inhibitory action on Aspergillus fumigatus.
abstract: The effect of ketoconazole on growth, sterol composition, in vitro sterol biosynthesis and P450-CO complex formation and its interaction with microsomal P450 was determined. On solid medium and in liquid medium ketoconazole inhibited Aspergillus fumigatus growth completely at 5 x 10(-5) M and 50% of the growth at 1.3 x 10(-5) M and 2.1 x 10(-5) M respectively. A close relationship between accumulation of 14 alpha-methyl sterols (eburicol, obtusifoliol and 14 alpha-methyl fecosterol) and depletion of ergosterol with growth arrest was observed in ketoconazole treated cultures. The half inhibitory concentration for in vitro ergosterol biosynthesis and half saturating concentration for type II binding spectrum of ketoconazole were calculated as 73.8 +/- 6.3 nM and 0.13 +/- 0.04 microM respectively. CO displacement studies revealed inhibition of CO-P450 complex formation by ketoconazole.
authors.affiliation: Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, UK.
authors.forename: K
authors.initials: K
authors.lastname: Venkateswarlu
authors.forename: S L
authors.initials: SL
authors.lastname: Kelly
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D002849:Chromatography, Gas; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007654:Ketoconazole / Q000008:administration & dosage / Q000494:pharmacology*; D013058:Mass Spectrometry; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D013261:Sterols / Q000096:biosynthesis / Q000378:metabolism; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D013261:Sterols; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole