Compound IKD-8344, a Selective Growth Inhibitor Against the Mycelial Form of Candida albicans, Isolated from Streptomyces sp. A6792

  • HWANG EUI IL (Bio Research Group, KT&G Central Research Institute) ;
  • YUN BONG SIK (Laboratory of Cellular Function Modulator, Korea Research Institute of Bioscience and Biotechnology) ;
  • YEO WOON HYUNG (Bio Research Group, KT&G Central Research Institute) ;
  • LEE SANG HAN (Laboratory of Cellular Function Modulator, Korea Research Institute of Bioscience and Biotechnology) ;
  • MOON JAE SUN (Laboratory of Cellular Function Modulator, Korea Research Institute of Bioscience and Biotechnology) ;
  • KIM YOUNG KOOK (Laboratory of Cellular Function Modulator, Korea Research Institute of Bioscience and Biotechnology) ;
  • LIM SE JIN (College of Pharmacy, Dongduk Women's University) ;
  • KIM SUNG UK (Laboratory of Cellular Function Modulator, Korea Research Institute of Bioscience and Biotechnology)
  • Published : 2005.08.01

Abstract

In the course of screening for selective growth inhibitors against the mycelial form of Candida albicans, we isolated a Streptomyces sp. A6792 from soils. The inhibitor was isolated from the above bacterium and identified through several spectral analyses with UV and mass spectrophotometries, and various NMR. The compound was determined to be a macrocyclic dilactone antibiotic, IKD-8344 (molecular weight: 844, molecular formula: $C_{48}H_{76}O_{12}$). The compound selectively inhibited the growth of mycelial form of C. albicans with an MIC of 6.25 ${\mu}g/ml$. It also exhibited strong inhibitory effect preferentially on the mycelial form of various Candida spp. including C. krusei, C. tropicalis, and C. lusitaniae, with MICs ranging from 1.56 to 25 ${\mu}g$/ml. Furthermore, the compound showed no significant toxicity against SPF ICR mice up to 60 mg/kg. These results suggest that IKD-8344 is a useful lead compound for the development of novel antifungal agents, based on the preferential growth inhibition against Candida spp.

Keywords

References

  1. Sudberg, P., N. Gow, and J. Berman. 2004. The distinct morphogenic states of Candida albicans. Trends Microbiol. 12: 317-324 https://doi.org/10.1016/j.tim.2004.05.008
  2. Sudoh, M., T. Yamazaki, K. Masucuchi, M. Taniguchi, N. Shimma, M. Arisawa, and H. Yamada-Okabe. 2000. Identification of a novel inhibitor specific to the fungal chitin synthase. J. Biol. Chem. 276: 32901-32906
  3. Cutler, J. E. 1991. Putative virulence factors of Candida albicans. Annu. Rev. Microbiol. 45: 187-218 https://doi.org/10.1146/annurev.mi.45.100191.001155
  4. Calderone, R. A. and W. A. Fonzi. 2001 Virulence factors of Candida albicans. Trends Microbiol. 9: 327-335 https://doi.org/10.1016/S0966-842X(01)02094-7
  5. Haynes, K. 2001. Virulence in Candida species. Trends Microbiol. 9: 591-596 https://doi.org/10.1016/S0966-842X(01)02237-5
  6. Wenzet, R. P. 1995. Nosocomial candidiasis: Risk factors and attributable mortality. Clin. Infect. Dis. 20: 1531-1534 https://doi.org/10.1093/clinids/20.6.1531
  7. Edmond, M. B., S. E. Wallace, D. K. Mcclish, M. A. Pfaller, R. N. Jones, and R. P. Wenzel. 1999. Nosocomial bloodstream infections in the United States hospitals: A three-year analysis. Clin. Infect. Dis. 29: 239-244 https://doi.org/10.1086/520192
  8. Pfaller, M. A., D. J. Diekema, R. N. Jones, H. S. Sader, A. C. Fluit, R. J. Hollis, and S. A. Messer. 2001. International surveillance of bloodstream infections due to Candida species; frequency of occurance and in vitro susceptibilities to fluconazole, ravuconazole, and voriconazole of isolates collected from 1997 through 1999 in the SENTRY antimicrobial surveillance program. J. Clin. Microbiol. 39: 3254-3259 https://doi.org/10.1128/JCM.39.9.3254-3259.2001
  9. Gow, N. A. R., A. J. P. Brown, and F. C. Odds. 2002. Fungal morphogenesis and host invasion. Curr. Opin. Microbiol. 5: 366-371 https://doi.org/10.1016/S1369-5274(02)00338-7
  10. Leberer, E., D. Harcus, J. D. Broadbent, K. L. Clark, D. Dignard, K. Ziegelbauer, A. Schmidt, N. A. R. Gow, A. J. P. Brown, and D. Y. Thomas. 1996. Signal transduction through homo logs of the Ste20p and Ste7p protein kinases can trigger hyphal formation in the pathogenic fungus Candida albicans. Proc. Natl. Acad. Sci. USA 93: 13217-13222
  11. Brown, A. J. P. and N. A. R. Gow. 1999. Regulatory networks controlling Candida albicans morphogenesis. Trends Microbiol. 7: 333-338 https://doi.org/10.1016/S0966-842X(99)01556-5
  12. Lo, H. T., J. R. Kohler, B. DiDomenico, D. Loebenberg, A. Cacciapuoti, and G. R. Fink. 1997. Nonfilamentous C. albicans mutants are avirulent. Cell 90: 939-949 https://doi.org/10.1016/S0092-8674(00)80358-X
  13. Gale, C. A., C. M. Bendel, M. McClellan, M. Hauser, J. M. Becker, J. Berman, and M. K. Hostetter. 1998. Linkage of adhesion, filamentous growth, and virulence in Candida albicans to a single gene, INTI. Science 279: 1355-1358 https://doi.org/10.1126/science.279.5355.1355
  14. Hwang, E. I., B. S. 'Vun, S. H. Lee, S. K. Kim, S. J. Lim, and S. U. Kim. 2004. 7-Oxostaurosporine selectively inhibit the mycelial form of Candida albicans. J. Microbiol. Biotechnol. 14: 1067-1070
  15. Mcginnis, M. R. and M. G. Rinaldi. 1986. Antifungal drugs: Mechanisms of action, drug resistance, susceptibility testing, and assays of activity in biological fluids, pp. 243-260. In V. Lorian (ed.), Antibiotics in Laboratory Medicine. Williams & Wilkins, Baltimore
  16. Locci, R. 1989. Streptomycetes and related genera, pp. 2451-2492. In S. T. Williams, M. E. Sharpe, and J. G. Holt (eds.), Bergey's Manual of Systematic Bacteriology, Vol. 4. Williams and Wilkins, Baltimore
  17. Minami, Y., K. I. Yoshida, R. Azuma, M. Nishii, J. I. Inagaki, and F. Nohara. 1992. Structure of a novel macrodiolide antibiotic IKD-8344. Tetrahedron Lett. 33: 7373-7376 https://doi.org/10.1016/S0040-4039(00)60191-0