The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp. and Microsporum canis

H. Vanden Bossche, J. Ausma, H. Bohets, K. Vermuyten, G. Willemsens, P. Marichal, L. Meerpoel, Frank Christopher Odds, M. Borgers

    Research output: Contribution to journalArticle

    32 Citations (Scopus)

    Abstract

    R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microspgrum canis at nanomolar concentrations, with 50% inhibitory concentrations IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 muM for itraconazole and 3.1 muM for R126638. Compared to itraconazole (IC50 = 3.5 muM), R126638 is a poor inhibitor of the 1alpha-hydroxylation of 25-hydroxyvitamin D-3 IC50 > 10 muM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D-3, and the conversion of 1,1,25-dihydroxyvitamin D-3, into polar metabolites. At concentrations up to 10 muM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11beta-hydroxylase (CYPHBII), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 muM, R126638 did not show clear inhibition of CYP1A2,CYP2A6,CYP26,CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.

    Original languageEnglish
    Pages (from-to)3272-3278
    Number of pages6
    JournalAntimicrobial Agents and Chemotherapy
    Volume48
    DOIs
    Publication statusPublished - 2004

    Keywords

    • HUMAN LIVER-MICROSOMES
    • IN-VITRO
    • ANTIFUNGAL AGENTS
    • STEROID-BIOSYNTHESIS
    • METABOLISM
    • ITRACONAZOLE
    • CYTOCHROME-P-450
    • 3-KETOSTEROIDS
    • VORICONAZOLE
    • KETOCONAZOLE

    Cite this

    The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp. and Microsporum canis. / Vanden Bossche, H.; Ausma, J.; Bohets, H.; Vermuyten, K.; Willemsens, G.; Marichal, P.; Meerpoel, L.; Odds, Frank Christopher; Borgers, M.

    In: Antimicrobial Agents and Chemotherapy, Vol. 48, 2004, p. 3272-3278.

    Research output: Contribution to journalArticle

    Vanden Bossche, H, Ausma, J, Bohets, H, Vermuyten, K, Willemsens, G, Marichal, P, Meerpoel, L, Odds, FC & Borgers, M 2004, 'The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp. and Microsporum canis', Antimicrobial Agents and Chemotherapy, vol. 48, pp. 3272-3278. https://doi.org/10.1128/AAC.48.9.3272-3278.2004
    Vanden Bossche, H. ; Ausma, J. ; Bohets, H. ; Vermuyten, K. ; Willemsens, G. ; Marichal, P. ; Meerpoel, L. ; Odds, Frank Christopher ; Borgers, M. / The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp. and Microsporum canis. In: Antimicrobial Agents and Chemotherapy. 2004 ; Vol. 48. pp. 3272-3278.
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    abstract = "R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microspgrum canis at nanomolar concentrations, with 50{\%} inhibitory concentrations IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 muM for itraconazole and 3.1 muM for R126638. Compared to itraconazole (IC50 = 3.5 muM), R126638 is a poor inhibitor of the 1alpha-hydroxylation of 25-hydroxyvitamin D-3 IC50 > 10 muM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D-3, and the conversion of 1,1,25-dihydroxyvitamin D-3, into polar metabolites. At concentrations up to 10 muM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11beta-hydroxylase (CYPHBII), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 muM, R126638 did not show clear inhibition of CYP1A2,CYP2A6,CYP26,CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.",
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    TY - JOUR

    T1 - The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp. and Microsporum canis

    AU - Vanden Bossche, H.

    AU - Ausma, J.

    AU - Bohets, H.

    AU - Vermuyten, K.

    AU - Willemsens, G.

    AU - Marichal, P.

    AU - Meerpoel, L.

    AU - Odds, Frank Christopher

    AU - Borgers, M.

    PY - 2004

    Y1 - 2004

    N2 - R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microspgrum canis at nanomolar concentrations, with 50% inhibitory concentrations IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 muM for itraconazole and 3.1 muM for R126638. Compared to itraconazole (IC50 = 3.5 muM), R126638 is a poor inhibitor of the 1alpha-hydroxylation of 25-hydroxyvitamin D-3 IC50 > 10 muM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D-3, and the conversion of 1,1,25-dihydroxyvitamin D-3, into polar metabolites. At concentrations up to 10 muM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11beta-hydroxylase (CYPHBII), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 muM, R126638 did not show clear inhibition of CYP1A2,CYP2A6,CYP26,CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.

    AB - R126638 is a novel triazole with in vitro activity similar to that of itraconazole against dermatophytes, Candida spp., and Malassezia spp. In animal models of dermatophyte infections, R126638 showed superior antifungal activity. R126638 inhibits ergosterol synthesis in Candida albicans, Trichophyton mentagrophytes, Trichophyton rubrum, and Microspgrum canis at nanomolar concentrations, with 50% inhibitory concentrations IC(50)s) similar to those of itraconazole. The decreased synthesis of ergosterol and the concomitant accumulation of 14alpha-methylsterols provide indirect evidence that R126638 inhibits the activity of CYP51 that catalyzes the oxidative removal of the 14alpha-methyl group of lanosterol or eburicol. The IC(50)s for cholesterol synthesis from acetate in human hepatoma cells were 1.4 muM for itraconazole and 3.1 muM for R126638. Compared to itraconazole (IC50 = 3.5 muM), R126638 is a poor inhibitor of the 1alpha-hydroxylation of 25-hydroxyvitamin D-3 IC50 > 10 muM). Micromolar concentrations of R126638 and itraconazole inhibited the 24-hydroxylation of 25-hydroxyvitamin D-3, and the conversion of 1,1,25-dihydroxyvitamin D-3, into polar metabolites. At concentrations up to 10 muM, R126638 had almost no effect on cholesterol side chain cleavage (CYP11A1), 11beta-hydroxylase (CYPHBII), 17-hydroxylase and 17,20-lyase (CYP17), aromatase (CYP19), or 4-hydroxylation of all-trans retinoic acid (CYP26). At 10 muM, R126638 did not show clear inhibition of CYP1A2,CYP2A6,CYP26,CYP2C8, CYP2C9, CYP2C10, CYP2C19, or CYP2E1. Compared to itraconazole, R126638 had a lower interaction potential with testosterone 6beta hydroxylation and cyclosporine hydroxylation, both of which are catalyzed by CYP3A4, whereas both antifungals inhibited the CYP3A4-catalyzed hydroxylation of midazolam similarly. The results suggest that R126638 has promising properties and merits further in vivo investigations for the treatment of dermatophyte and yeast infections.

    KW - HUMAN LIVER-MICROSOMES

    KW - IN-VITRO

    KW - ANTIFUNGAL AGENTS

    KW - STEROID-BIOSYNTHESIS

    KW - METABOLISM

    KW - ITRACONAZOLE

    KW - CYTOCHROME-P-450

    KW - 3-KETOSTEROIDS

    KW - VORICONAZOLE

    KW - KETOCONAZOLE

    U2 - 10.1128/AAC.48.9.3272-3278.2004

    DO - 10.1128/AAC.48.9.3272-3278.2004

    M3 - Article

    VL - 48

    SP - 3272

    EP - 3278

    JO - Antimicrobial Agents and Chemotherapy

    JF - Antimicrobial Agents and Chemotherapy

    SN - 0066-4804

    ER -