Mode of Action of Antifungals of Use in Immunocompromised Patients. Focus on Candida Glabrata and Histoplasma Capsulatum

Bossche, H. Vanden; Marichal, Patrick; Gorrens, J.; Bellens, Danny; Coene, M.‐C.; Lauwers, W; Jeune, L. Le; Moereels, Henri; Janßen, Paul

doi:10.1007/978-1-4613-0655-9_22

Cited by 16 publications

(21 citation statements)

References 37 publications

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“…Obtusifolione was quantitatively the major sterol found in itraconazole-treated C. neofornans; the effects of the antifungal agent on this yeast therefore resemble those previously observed with H. capsulatum (20). Prerequisites for both the condensing and liquefying effects of sterols in membranes are a planar ring system and a long flexible chain at C-17 (8).…”

Section: Resultssupporting

confidence: 64%

“…neoforinans (this study) and in the yeast form of H. capsulatum (20) may explain the high sensitivity of both yeasts to itraconazole. Indeed, 50% inhibition of growth is achieved at concentrations as low as 3.2 nM (this study) and 1.7 nM (20), respectively.…”

Section: Resultsmentioning

confidence: 57%

“…Indeed, incubation in the presence of itraconazole results in a decreased ergosterol synthesis coinciding with an accumulation of 14- methylglutaryl-coenzyme A reductase as has been described for, e.g., 24,25-epoxidocholesterol (15). As with A. fumigatus (19), H. capsulatum (20), and Malassezia ovale (23), itraconazole induces the accumulation of large amounts of eburicol. Membrane integrity requires the inserted sterol component to lack C-4 methyl groups (10).…”

Section: Resultsmentioning

confidence: 96%

“…Itraconazole is an ergosterol biosynthesis inhibitor in many fungi (18,(20)(21)(22). This triazole antifungal agent has been shown to inhibit the cytochrome P-450-dependent 14a-demethylation of lanosterol or 24-methylene-24,25-dihydrolanosterol (eburicol) in, for example, Candida albicans, Candida glabrata, Candida lusitaniae, Aspergillus fumigatus, Trichophyton mentagrophytes, and Histoplasma capsulatum.…”

mentioning

confidence: 99%

“…For example, complete inhibition of ergosterol synthesis was achieved in C. albicans after 1 h of contact with itraconazole concentrations as low as 10 nM (21). After 24 h of incubation, ergosterol synthesis was completely blocked at 30 nM (18), and, at 300 nM ergosterol, concentrations decreased below the detection level, i.e., < 5 fg per cell (20).…”

mentioning

confidence: 99%

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Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans

Bossche

Marichal

Jeune

et al. 1993

Antimicrob Agents Chemother

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As in other pathogenic fungi, the major sterol synthesized by Cryptococcus neoformans var. neoformans is ergosterol. This yeast also shares with most pathogenic fungi a susceptibility of its cytochrome P-450-dependent ergosterol synthesis to nanomolar concentrations of itraconazole. Fifty percent inhibition of ergosterol synthesis was reached after 16 h of growth in the presence of 6.0 +/- 4.7 nM itraconazole, and complete inhibition was reached at approximately 100 nM itraconazole. This inhibition coincided with the accumulation of mainly eburicol and the 3-ketosteroid obtusifolione. The radioactivity incorporated from [14C]acetate in both compounds represents 64.2% +/- 12.9% of the radioactivity incorporated into the sterols plus squalene extracted from cells incubated in the presence of 10 nM itraconazole. The accumulation of obtusifolione as well as eburicol indicates that itraconazole inhibits not only the 14 alpha-demethylase but also (directly or indirectly) the NADPH-dependent 3-ketosteroid reductase, i.e., the enzyme catalyzing the last step in the demethylation at C-4. This latter inhibition obviates the synthesis of 4,4-demethylated 14 alpha-methylsterols that may function at least partly as surrogates of ergosterol. Eburicol and obtusifolione are unable to support cell growth, and the 3-ketosteroid has been shown to disturb membranes. The complete inhibition of ergosterol synthesis and the accumulation of the 4,4,14-trimethylsterol and of the 3-ketosteroid together with the absence of sterols, such as 14 alpha-methylfecosterol and lanosterol, which can partly fulfill some functions of ergosterol, are at the origin of the high activity of itraconazole against C. neoformans. Fifty percent inhibition of growth achieved after 16 h of incubation in the presence of 3.2 +/- 2.6 nM itraconazole.

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 57%