Mycobiology

The Korean Society of Mycology (한국균학회)
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In Vitro Antifungal Activity and Mode of Action of 2',4'-Dihydroxychalcone against Aspergillus fumigatus

  • Seo, Young Ho (College of Pharmacy, Keimyung University) ;
  • Kim, Sung-Su (Department of Biomedical Laboratory Science, Daejeon University) ;
  • Shin, Kwang-Soo (Division of Life Sciences, Daejeon University)
  • Received : 2015.03.04
  • Accepted : 2015.04.08
  • 발행 : 2015.06.30
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초록

2',4'-Dihydroxychalcone (2',4'-DHC) was identified from a heat shock protein 90 (Hsp90)-targeting library as a compound with Hsp90 inhibitory and antifungal effects. In the presence of 2',4'-DHC ($8{\mu}g/mL$), radial growth of Aspergillus fumigatus was inhibited 20% compared to the control, and green pigmentation was completely blocked. The expression of the conidiation-associated genes abaA, brlA, and wetA was significantly decreased (approximately 3- to 5-fold) by treatment with 2',4'-DHC. The expression of calcineurin signaling components, cnaA and crzA, was also significantly reduced. The inhibitory effects of 2',4'-DHC on metabolic activity and mycelial growth were significantly enhanced by combination treatment with itraconazole and caspofungin. Docking studies indicated that 2',4'-DHC bind to the ATPase domain of Hsp90. These results suggest that 2',4'-DHC act as an Hsp90-calcinurin pathway inhibitor.

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참고문헌

  1. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26:781-803. https://doi.org/10.1086/513943
  2. Latge JP. Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev 1999;12:310-50.
  3. Brajtburg J, Bolard J. Carrier effects on biological activity of amphotericin B. Clin Microbiol Rev 1996;9:512-31.
  4. Cappelletty D, Eiselstein-McKitrick K. The echinocandins. Pharmacotherapy 2007;27:369-88. https://doi.org/10.1592/phco.27.3.369
  5. Howard SJ, Cerar D, Anderson MJ, Albarrag A, Fisher MC, Pasqualotto AC, Laverdiere M, Arendrup MC, Perlin DS, Denning DW. Frequency and evolution of azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis 2009;15:1068-76. https://doi.org/10.3201/eid1507.090043
  6. Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 2005; 309:2185-9. https://doi.org/10.1126/science.1118370
  7. Lamoth F, Juvvadi PR, Gehrke C, Steinbach WJ. In vitro activity of calcineurin and heat shock protein 90 inhibitors against Aspergillus fumigatus azole- and echinocandin-resistant strains. Antimicrob Agents Chemother 2013;57:1035-9. https://doi.org/10.1128/AAC.01857-12
  8. Lee T, Seo YH. Targeting the hydrophobic region of Hsp90's ATP binding pocket with novel 1,3,5-triazines. Bioorg Med Chem Lett 2013;23:6427-31. https://doi.org/10.1016/j.bmcl.2013.09.050
  9. Jeong CH, Park HB, Jang WJ, Jung SH, Seo YH. Discovery of hybrid Hsp90 inhibitors and their anti-neoplastic effects against gefitinib-resistant non-small cell lung cancer (NSCLC). Bioorg Med Chem Lett 2014;24:224-7. https://doi.org/10.1016/j.bmcl.2013.11.034
  10. Svetaz L, Tapia A, Lopez SN, Furlan RL, Petenatti E, Pioli R, Schmeda-Hirschmann, G, Zacchino SA. Antifungal chalcones and new caffeic acid esters from Zuccagnia punctata acting against soybean infecting fungi. J Agric Food Chem 2004;52:3297-300. https://doi.org/10.1021/jf035213x
  11. Svetaz L, Aguero MB, Alvarez S, Luna L, Feresin G, Derita M, Tapia A, Zacchino S. Antifungal activity of Zuccagnia punctate Cav.: evidence for the mechanism of action. Planta Med 2007;73:1074-80. https://doi.org/10.1055/s-2007-981561
  12. Baek KH, Karki R, Lee ES, Na Y, Kwon Y. Synthesis and investigation of dihydroxychalcones as calpain and cathepsin inhibitors. Bioorg Chem 2013;51:24-30. https://doi.org/10.1016/j.bioorg.2013.09.002
  13. Meletiadis J, Meis JF, Mouton JW, Donnelly JP, Verweij PE. Comparison of NCCLS and 3-(4,5-dimethyl-2-thiazyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) methods of in vitro susceptibility testing of filamentous fungi and development of a new simplified method. J Clin Microbiol 2000;38:2949-54.
  14. Kafer E. Meiotic and mitotic recombination in Aspergillus and its chromosomal aberrations. Adv Genet 1977;19:33-131. https://doi.org/10.1016/S0065-2660(08)60245-X
  15. Kim SS, Kim YH, Shin KS. The developmental regulators, FlbB and FlbE, are involved in the virulence of Aspergillus fumigatus. J Microbiol Biotechnol 2013;23:766-70. https://doi.org/10.4014/jmb.1301.01002
  16. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the ${2^{{-\Delta}{\Delta}C}}_T$ method. Methods 2001;25:402-8. https://doi.org/10.1006/meth.2001.1262
  17. Coyle CM, Kenaley SC, Rittenour WR, Panaccione DG. Association of ergot alkaloids with conidiation in Aspergillus fumigatus. Mycologia 2007;99:804-11. https://doi.org/10.3852/mycologia.99.6.804
  18. Tao L, Yu JH. AbaA and WetA govern distinct stages of Aspergillus fumigatus development. Microbiology 2011;157(Pt2):313-26. https://doi.org/10.1099/mic.0.044271-0
  19. Steinbach WJ, Cramer RA Jr, Perfect BZ, Asfaw YG, Sauer TC, Najvar LK, Kirkpatrick WR, Patterson TF, Benjamin DK Jr, Heitman J, et al. Calcineurin controls growth, morphology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell 2006;5:1091-103. https://doi.org/10.1128/EC.00139-06
  20. Steinbach WJ, Cramer RA Jr, Perfect BZ, Henn C, Nielsen K, Heitman J, Perfect JR. Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus. Antimicrob Agents Chemother 2007;51:2979-81. https://doi.org/10.1128/AAC.01394-06
  21. Onyewu C, Wormley FL Jr, Perfect JR, Heitman J. The calcineurin target, Crz1, functions in azole tolerance but is not required for virulence of Candida albicans. Infect Immun 2004;72:7330-3. https://doi.org/10.1128/IAI.72.12.7330-7333.2004
  22. Lamoth F, Juvvadi PR, Fortwendel JR, Steinbach WJ. Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus. Eukaryot Cell 2012;11:1324-32. https://doi.org/10.1128/EC.00032-12