Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지

Anti-Candida Activity of YH-1715R, a New Triazole Derivative

  • Park, Kang-Sik (Department of Biochemistry, Yonsei Proteome Research Center, and Bioproducts Research Center, Yonsei University) ;
  • Kang, Heui-Il (Yuhan Research Center, Yuhan Corporation) ;
  • Lee, Jong-Wook (Yuhan Research Center, Yuhan Corporation) ;
  • Paik, Young-Ki (Department of Biochemistry, Yonsei Proteome Research Center, and Bioproducts Research Center, Yonsei University)
  • Published : 2004.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

YH-1715R, (2R,3R)-2-(2,4-difluorophenyl)-3-(3-methoxy-1,2,4-isothiazol-3-yl-thio)-1-( 1H-1,2,4-triazol-l-yl)-2-butanol, a new triazole derivative obtained by the structural modification of fluconazole, was found to exhibit potent anti-Candida activity against a wide variety of Candida albicans (C. albicans) (MIC: 0.4-12.5 mg/l). To investigate the mode of action of YH-1715R, its effect on ergosterol biosynthesis in cell-free extracts and whole cells of C. albicans was examined. The inhibitory activity of YH-1715R was approximately ten-fold higher than that of fluconazole. To determine the primary action mechanism of YH-1715R, its inhibitory activity against lanosterol $14\alpha$-demethylase (14$\alpha$-DM), a major target for azole, was measured using gas-liquid chromatography. YH-1715R and fluconazole were found to inhibit 14a-DM with an $IC_{50}$ of 0.015 $\mu$M and 0.01$8\mu$M, respectively, plus the mode of inhibition of YH-1715R and fluconozole was noncompetitive with a $K_i$ of 0.0533$\mu$M and 0.0975$\mu$M.

Keywords

References

  1. Clin. Microbiol. Infect. v.7 Uncommon opportunistic fungi: New Nosocomial threats Groll, A. H.;T. J. Walsh
  2. Biochem. J. v.266 Interaction of azole antifungal antibiotics with cytochrome P-450-dependent 14α-sterol demethylase purified from Candida albicans Hitchcock, C. A.;K. Dickinson;S. B. Brown;E. G. V. Evans;D. J. Adams https://doi.org/10.1042/bj2660475
  3. Korea Patent Application: KP 94-4918. Kang, H.-I.;J.W.Lee
  4. FEMS Microbiol. Lett. v.149 Differential inhibition of Candida albicans CYP51 by stereoisomers of azole antifungals Lamb, D. C.;D. E .Kelly;B. C .Baldwin;F. Gozzo;P. Boscott;W. G. Richards;S. L. Kelly
  5. Biochem. Pharmacol. v.57 Biochemical basis for a cholesterol-lowering activity of 2-[2"-(1",3"-dioxolane)]-2-methyl-4-2(2'-oxo-1'-pyrrolidinyl)-6-nitro-2H-1-benzopyran (SKP-450), a novel antihypertensive agent Lee, E. Y.;D. M. Lim;S. E. Yoo;D. K. Kim;Y. K. Paik https://doi.org/10.1016/S0006-2952(98)00321-9
  6. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts - Approved Standard M27-A. National Committee for Clinical Laboratory Standards
  7. Med. Mycol. v.37 Inhibition of sterol 14 ${\alpha}$-demethylation of Candida albicans with NND-502, a novel optically active imidazole antimycotic agent Niwano, Y.;H. Koga;K. Kodama;K. Kanai;T. Miyazaki;H. Yamaguchi https://doi.org/10.1046/j.1365-280X.1999.00243.x
  8. J. Antimicrob. Chemother v.43 Differential inhibitory effects of protoberberines on sterol and chitin biosyntheses in Candida albicans Park, K. S.;K. C. Kang;J. H. Kim;D. J. Adams;T. N. Johng;Y. K. Paik https://doi.org/10.1093/jac/43.5.667
  9. J. Antimicrob. Chemother. v.47 HWY-289, a novel semi-synthetic protoberberine derivative with multiple target sites in Candida albicans Park, K. S.;K. C. Kang;K. Y. Kim;P. Y. Jeong;J. H. Kim;D. J. Adams;J. H. Kim;Y. K. Paik https://doi.org/10.1093/jac/47.5.513
  10. Lancet Infect. Dis. v.2 Resistance of Candida species to antifungal agents: Molecular mechanisms and clinical consequences Sanglard, D. F.;C. Odds https://doi.org/10.1016/S1473-3099(02)00181-0
  11. Mycoses v.41 Cytochromes P450 in fungi Vanden Bossche, H.;L. Koymans https://doi.org/10.1111/j.1439-0507.1998.tb00581.x
  12. Biochem. Pharmacol. v.36 Interaction of azole antifungal agents with cytochrome P45014DM purified from Saccharomyces cerevisiae microsomes Yoshida, Y.;Y. Aoyama https://doi.org/10.1016/0006-2952(87)90694-0