Selective inhibition of 14 alpha-desmethyl sterol synthesis in Candida albicans by terconazole, a new triazole antimycotic.

Abstract

Terconazole, a new broad spectrum antimycotic triazole derivative, has been shown to have potent activity against Candida albicans in vitro and to be effective in animal models of yeast infections. The present study explored a possible mechanism of anticandidal activity of terconazole. The compound inhibited production of 14 alpha-desmethyl sterols (e.g. ergosterol) in C. albicans at concentrations (IC50 = 3-6 x 10(-9) M) lower than those inhibiting the in-vitro growth of the yeast. There was concomitant accumulation of methylated sterols, (e.g. lanosterol), which are considered detrimental to normal yeast cell membrane function. Terconazole stimulated incorporation of 14C-acetate into triglycerides, but had no other effect on C. albicans lipid metabolism. At concentrations greater than or equal to 10(-6)M terconazole inhibited the oxidation of 14C-acetate into 14CO2 in C. albicans although the mechanism for this effect remains unclear. These data indicate that terconazole is a specific inhibitor of yeast C-14 desmethyl sterol production in C. albicans. Furthermore, terconazole reduced cytochrome P-450 levels in yeast microsomes at concentrations 10,000-fold below those at which it showed effects on rabbit liver microsomes. These data indicate a species specificity for the biochemical actions of terconazole. The C-14 alpha-desmethylase system in yeast cell membranes is cytochrome P-450 associated. Thus, terconazole, was a potent inhibitor of C-14 desmethyl sterol synthesis. This effect could contribute to the anticandidal activity of the drug.

• Authors: D M Isaacson, E L Tolman, A J Tobia, M E Rosenthale, J L McGuire, H Vanden Bossche, P A Janssen
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 21 Issue 3 Pg. 333-43 (Mar 1988) ISSN: 0305-7453 [Print] England
• PMID: 3129389 (Publication Type: Journal Article)

Chemical References

• Acetates
• Antifungal Agents
• Sterols
• Triazoles
• Triglycerides
• terconazole
• Carbon Dioxide
• Cytochrome P-450 Enzyme System
• Oxidoreductases
• Sterol 14-Demethylase

Topics

• Acetates (metabolism)
• Antifungal Agents (pharmacology)
• Candida albicans (drug effects, metabolism)
• Carbon Dioxide (metabolism)
• Cytochrome P-450 Enzyme System (analysis)
• Oxidation-Reduction
• Oxidoreductases (antagonists & inhibitors)
• Sterol 14-Demethylase
• Sterols (biosynthesis)
• Triazoles (pharmacology)
• Triglycerides (biosynthesis)