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. 1997 Nov;41(11):2492–2496. doi: 10.1128/aac.41.11.2492

A new triazole, voriconazole (UK-109,496), blocks sterol biosynthesis in Candida albicans and Candida krusei.

H Sanati 1, P Belanger 1, R Fratti 1, M Ghannoum 1
PMCID: PMC164150  PMID: 9371355

Abstract

Voriconazole (UK-109,496) is a novel triazole derivative with potent broad-spectrum activity against various fungi, including some that are inherently resistant to fluconazole, such as Candida krusei. In this study we compared the effect of subinhibitory concentrations of voriconazole 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. Voriconazole MICs ranged from 0.003 to 4 microg/ml, while fluconazole MICs ranged from 0.25 to >64 microg/ml. To investigate the effects of voriconazole 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. Voriconazole 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). Gas-liquid chromatographic analysis revealed profound changes in the sterol profiles of both C. albicans strains and of C. krusei in response to voriconazole. This antifungal agent exerted a similar effect on the sterol compositions of both fluconazole-susceptible and -resistant C. albicans strains. Interestingly, a complete inhibition of ergosterol synthesis and accumulation of its biosynthetic precursors were observed in both strains treated with voriconazole. In contrast, fluconazole partially inhibited ergosterol synthesis. Analysis of sterols obtained from a fluconazole-resistant C. albicans strain grown in the presence of different concentrations 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 intermediates: squalene, 4,14-dimethylzymosterol, and 24-methylenedihydrolanosterol. Accumulation of these methylated sterols is consistent with the premise that this agent functions by inhibiting fungal P-450-dependent 14alpha-demethylase. As expected, treating C. krusei with fluconazole minimally inhibited ergosterol synthesis. Importantly, our data indicate that voriconazole is more effective than fluconazole in blocking candidal sterol biosynthesis, consistent with the different antifungal potencies of these compounds.

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Selected References

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  1. Arndt C. A., Walsh T. J., McCully C. L., Balis F. M., Pizzo P. A., Poplack D. G. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis. 1988 Jan;157(1):178–180. doi: 10.1093/infdis/157.1.178. [DOI] [PubMed] [Google Scholar]
  2. Beggs W. H. Comparison of miconazole- and ketoconazole-induced release of K+ from Candida species. J Antimicrob Chemother. 1983 Apr;11(4):381–383. doi: 10.1093/jac/11.4.381. [DOI] [PubMed] [Google Scholar]
  3. Bodey G. P. Fungal infections in cancer patients. Ann N Y Acad Sci. 1988;544:431–442. doi: 10.1111/j.1749-6632.1988.tb40441.x. [DOI] [PubMed] [Google Scholar]
  4. Cope J. E. Mode of action of miconazole on Candida albicans: effect on growth, viability and K+ release. J Gen Microbiol. 1980 Jul;119(1):245–251. doi: 10.1099/00221287-119-1-245. [DOI] [PubMed] [Google Scholar]
  5. Georgopapadakou N. H., Walsh T. J. Antifungal agents: chemotherapeutic targets and immunologic strategies. Antimicrob Agents Chemother. 1996 Feb;40(2):279–291. doi: 10.1128/aac.40.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ghannoum M. A. Mechanisms potentiating Candida infections. A review. Mycoses. 1988 Nov;31(11):543–557. doi: 10.1111/j.1439-0507.1988.tb04408.x. [DOI] [PubMed] [Google Scholar]
  7. Ghannoum M. A., Moussa N. M., Whittaker P., Swairjo I., Abu-Elteen K. H. Subinhibitory concentration of octenidine and pirtenidine: influence on the lipid and sterol contents of Candida albicans. Chemotherapy. 1992;38(1):46–56. doi: 10.1159/000238941. [DOI] [PubMed] [Google Scholar]
  8. Ghannoum M. A., Spellberg B. J., Ibrahim A. S., Ritchie J. A., Currie B., Spitzer E. D., Edwards J. E., Jr, Casadevall A. Sterol composition of Cryptococcus neoformans in the presence and absence of fluconazole. Antimicrob Agents Chemother. 1994 Sep;38(9):2029–2033. doi: 10.1128/aac.38.9.2029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Marriott M. S. Isolation and chemical characterization of plasma membranes from the yeast and mycelial forms of Candida albicans. J Gen Microbiol. 1975 Jan;86(1):115–132. doi: 10.1099/00221287-86-1-115. [DOI] [PubMed] [Google Scholar]
  10. Pancaldi S., Dall'Olio G., Poli F., Fasulo M. P. Stimulation of the autophagic activity in blastospores of Candida albicans exposed in vitro to fluconazole. Microbios. 1994;80(322):55–61. [PubMed] [Google Scholar]
  11. Redding S., Smith J., Farinacci G., Rinaldi M., Fothergill A., Rhine-Chalberg J., Pfaller M. Resistance of Candida albicans to fluconazole during treatment of oropharyngeal candidiasis in a patient with AIDS: documentation by in vitro susceptibility testing and DNA subtype analysis. Clin Infect Dis. 1994 Feb;18(2):240–242. doi: 10.1093/clinids/18.2.240. [DOI] [PubMed] [Google Scholar]
  12. Sabra R., Branch R. A. Amphotericin B nephrotoxicity. Drug Saf. 1990 Mar-Apr;5(2):94–108. doi: 10.2165/00002018-199005020-00003. [DOI] [PubMed] [Google Scholar]
  13. Selik R. M., Starcher E. T., Curran J. W. Opportunistic diseases reported in AIDS patients: frequencies, associations, and trends. AIDS. 1987 Sep;1(3):175–182. [PubMed] [Google Scholar]
  14. Stern J. J., Hartman B. J., Sharkey P., Rowland V., Squires K. E., Murray H. W., Graybill J. R. Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med. 1988 Oct;85(4):477–480. doi: 10.1016/s0002-9343(88)80081-0. [DOI] [PubMed] [Google Scholar]
  15. Sud I. J., Feingold D. S. Heterogeneity of action of mechanisms among antimycotic imidazoles. Antimicrob Agents Chemother. 1981 Jul;20(1):71–74. doi: 10.1128/aac.20.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sud I. J., Feingold D. S. Mechanisms of action of the antimycotic imidazoles. J Invest Dermatol. 1981 Jun;76(6):438–441. doi: 10.1111/1523-1747.ep12521036. [DOI] [PubMed] [Google Scholar]
  17. Vanden Bossche H., Marichal P., Le Jeune L., Coene M. C., Gorrens J., Cools W. Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans. Antimicrob Agents Chemother. 1993 Oct;37(10):2101–2105. doi: 10.1128/aac.37.10.2101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Vandenheuvel F. A., Court A. S. Reference high-efficiency nonpolar packed columns for the gas-liquid chromatography of nanogram amounts of steroids. I. Retention time data. J Chromatogr. 1968 Dec 17;38(4):439–459. doi: 10.1016/0021-9673(68)85073-3. [DOI] [PubMed] [Google Scholar]
  19. Wey S. B., Mori M., Pfaller M. A., Woolson R. F., Wenzel R. P. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Arch Intern Med. 1988 Dec;148(12):2642–2645. doi: 10.1001/archinte.148.12.2642. [DOI] [PubMed] [Google Scholar]

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