H. Sanati et al., A NEW TRIAZOLE, VORICONAZOLE (UK-109,496), BLOCKS STEROL BIOSYNTHESISIN CANDIDA-ALBICANS AND CANDIDA-KRUSEI, Antimicrobial agents and chemotherapy, 41(11), 1997, pp. 2492-2496
Voriconazole (UK-109,496) is a novel triazole derivative with potent b
road-spectrum activity against various fungi, including some that are
inherently resistant to fluconazole, such as Candida krusei. In this s
tudy we compared the effect of subinhibitory concentrations of voricon
azole and fluconazole on sterol biosynthesis of fluconazole-resistant
and -susceptible Candida albicans strains, as well as C.krusei, in an
effort to delineate the precise mode of action of voriconazole. Vorico
nazole MICs ranged from 0.003 to 4 mu g/ml, while fluconazole MICs ran
ged from 0.25 to >64 mu g/ml. To investigate the effects of voriconazo
le and fluconazole on candidal sterols, yeast cells were grown in the
absence and presence of antifungals. In untreated C. albicans controls
, ergosterol was the major sterol (accounting for 53.6% +/- 2.2% to 71
.7% +/- 7.8% of the total) in C. albicans and C. krusei strains. There
was no significant difference between the sterol compositions of the
fluconazole-susceptible and -resistant C. albicans isolates. Voriconaz
ole treatment led to a decrease in the total sterol content of both C.
albicans strains tested. In contrast, exposure to fluconazole did not
result in a significant reduction in the total sterol content of the
three candidal strains tested (P > 0.5). Sas-liquid chromatographic an
alysis revealed profound changes in the sterol profiles of both C. alb
icans strains and of C. krusei in response to voriconazole. This antif
ungal agent exerted a similar effect on the sterol compositions of bot
h fluconazole-susceptible ana -resistant C. albicans strains. Interest
ingly, a complete inhibition of ergosterol synthesis and accumulation
of its biosynthetic precursors were observed in both strains treated w
ith voriconazole. In contrast, fluconazole partially inhibited ergoste
rol synthesis. Analysis of sterols obtained from a fluconazole-resista
nt C. albicans strain grown in the presence of different concentration
s of voriconazole showed that this agent inhibits ergosterol synthesis
in a dose-dependent manner. In C. krusei, voriconazole significantly
inhibited ergosterol synthesis (over 75% inhibition). C. krusei cells
treated with voriconazole accumulated the following biosynthetic inter
mediates: squalene, 4,14-dimethylzymosterol, and 24-methylenedihydrola
nosterol. Accumulation of these methylated sterols is consistent with
the premise that this agent functions by inhibiting fungal P-450-depen
dent 14 alpha-demethylase. As expected, treating C. krusei with flucon
azole minimally inhibited ergosterol synthesis. Importantly, our data
indicate that voriconazole is more effective than fuconazole in blocki
ng candidal sterol biosynthesis, consistent with the different antifun
gal potencies of these compounds.