Y132H substitution in Candida albicans sterol 14 alpha-demethylase confersfluconazole resistance by preventing binding to haem

Fungal cytochrome P450 sterol 14 alpha-demethylase (CYP51) is required for ergosterol biosynthesis and is the target for azole antifungal compounds. T he amino acid substitution Y132H in CYP51 from clinical isolates of Candida albicans can cause fluconazole resistance by a novel change in the protein . Fluconazole binding to the mutant protein did not involve normal interact ion with haem as shown by inducing a Type I spectral change. This contraste d to the wild-type protein where fluconazole inhibition was reflected in co ordination to haem as a sixth ligand and where the typical Type II spectrum was obtained. The Y132H substitution occurred without drastic perturbation of the haem environment or activity allowing resistant mutants to produce ergosterol and retain fitness, an efficient strategy for resistance in natu re. (C) 1999 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.