Titre
Azole susceptibility and hyphal formation in a cytochrome P-450-deficient mutant of Candida albicans
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Lees, N. D.
Auteure/Auteur
Broughton, M. C.
Auteure/Auteur
Sanglard, D.
Auteure/Auteur
Bard, M.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
0066-4804
Statut éditorial
Publié
Date de publication
1990-05
Volume
34
Numéro
5
Première page
831
Dernière page/numéro d’article
6
Notes
Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S. --- Old month value: May
Journal Article
Research Support, U.S. Gov't, P.H.S. --- Old month value: May
Résumé
A cytochrome P-450-deficient mutant of Candida albicans, strain D10, was employed to study the mode of action of imidazole antifungal agents. This mutant accumulates exclusively 14-alpha-methylsterols, resulting in a sterol profile which mimics that of azole-treated wild-type strains. Since the widely accepted primary effect of imidazoles is the inhibition of cytochrome P-450-mediated demethylation of the ergosterol precursor lanosterol, strain D10 and its wild-type revertant, strain D10R, were grown in the presence of concentrations of clotrimazole, miconazole, and ketoconazole known to inhibit demethylation. The growth of strain D10 was unaffected by these antifungal agents, while that of strain D10R was significantly reduced. At higher azole concentrations (which are known to exert a direct, disruptive action on the cell membrane), the growth of both strains was immediately and completely inhibited by clotrimazole and miconazole. Ketoconazole was membrane disruptive only for strain D10; this is the first report of a direct membrane effect for this drug. Because hyphal formation has been implicated in the pathogenesis of C. albicans and because it has been shown to be inhibited by azoles, the hypha-forming capability of strain D10 was examined. Strain D10 was shown to be seriously defective in hyphal formation, suggesting that this function may be dependent on the 14-alpha-demethylation of lanosterol. The results of this study suggest that inhibition of lanosterol demethylation per se is neither fungicidal nor fungistatic, although the growth rate is reduced. In addition, the substitution of 14-alpha-methylsterols for ergosterol results in defective hyphal formation and in a cell that is more susceptible to membrane-active agents such as ketoconazole.
Sujets
PID Serval
serval:BIB_CA9648A4E5BB
PMID
Date de création
2008-01-25T13:40:21.046Z
Date de création dans IRIS
2025-05-20T22:44:45Z