Comparison of D0870, a new triazole antifungal agent, to fluconazole for inhibition of Candida albicans cytochrome P-450 by using in vitro assays.
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.
Venkateswarlu
K
K
Department of Molecular Biology and Biotechnology, Krebs Institute for Biomolecular Research, Sheffield University, United Kingdom.
Denning
D W
DW
Manning
N J
NJ
Kelly
S L
SL
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*
D000935:Antifungal Agents; D014230:Triazoles; C058219:ICI 195739; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D004875:Ergosterol