Skip to main content
SpringerLink
Log in

Chemosensitization of Aflatoxigenic Fungi to Antimycin A and Strobilurin Using Salicylaldehyde, a Volatile Natural Compound Targeting Cellular Antioxidation System

  • Published:
Mycopathologia Aims and scope Submit manuscript

Abstract

Various species of fungi in the genus Aspergillus are the most common causative agents of invasive aspergillosis and/or producers of hepato-carcinogenic mycotoxins. Salicylaldehyde (SA), a volatile natural compound, exhibited potent antifungal and anti-mycotoxigenic activities to A. flavus and A. parasiticus. By exposure to the volatilized SA, the growth of A. parasiticus was inhibited up to 10–75% at 9.5 mM ≤ SA ≤ 16.0 mM, while complete growth inhibition was achieved at 19.0 mM ≤ SA. Similar trends were also observed with A. flavus. The aflatoxin production, i.e., aflatoxin B1 and B2 (AFB1, AFB2) for A. flavus and AFB1, AFB2, AFG1, and AFG2 for A. parasiticus, in the SA-treated (9.5 mM) fungi was reduced by ~13–45% compared with the untreated control. Using gene deletion mutants of the model yeast Saccharomyces cerevisiae, we identified the fungal antioxidation system as the molecular target of SA, where sod1Δ [cytosolic superoxide dismutase (SOD)], sod2Δ (mitochondrial SOD), and glr1Δ (glutathione reductase) mutants showed increased sensitivity to this compound. Also sensitive was the gene deletion mutant, vph2Δ, for the vacuolar ATPase assembly protein, suggesting vacuolar detoxification plays an important role for fungal tolerance to SA. In chemosensitization experiments, co-application of SA with either antimycin A or strobilurin (inhibitors of mitochondrial respiration) resulted in complete growth inhibition of Aspergillus at much lower dose treatment of either agent, alone. Therefore, SA can enhance antifungal activity of commercial antifungal agents required to achieve effective control. SA is a potent antifungal and anti-aflatoxigenic volatile that may have some practical application as a fumigant.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Martin MD, Rex JH. Antifungal drug resistance: a focus on Candida. Clin Updates Fungal Infec. 1997;1:238–41.

    Google Scholar 

  2. Moore CB, Sayres N, Mosquera J, et al. Antifungal drug resistance in Aspergillus. J Infect. 2000;41:203–20.

    Article  PubMed  CAS  Google Scholar 

  3. Cowen LE, Kohn LM, Anderson JB. Divergence in fitness and evolution of drug resistance in experimental populations of Candida albicans. J Bacteriol. 2001;183:2971–8.

    Article  PubMed  CAS  Google Scholar 

  4. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501–17.

    PubMed  CAS  Google Scholar 

  5. Luo H, Morsomme P, Boutry M. The two major types of plant plasma membrane H+ -ATPases show different enzymatic properties and confer differential pH sensitivity of yeast growth. Plant Physiol. 1999;119:627–34.

    Article  PubMed  CAS  Google Scholar 

  6. Beekrum S, Govinden R, Padayachee T, et al. Naturally occurring phenols: a detoxification strategy for fumonisin B1. Food Addit Contam. 2003;20:490–3.

    Article  PubMed  CAS  Google Scholar 

  7. Kim JH, Yu J, Mahoney N, et al. Elucidation of the functional genomics of antioxidant-based inhibition of aflatoxin biosynthesis. Int J Food Microbiol. 2008;122:49–60.

    Article  PubMed  CAS  Google Scholar 

  8. Aziz NH, Farag SE, Mousa LA, et al. Comparative antibacterial and antifungal effects of some phenolic compounds. Microbios. 1998;93:43–54.

    PubMed  CAS  Google Scholar 

  9. Curir P, Dolci M, Dolci P, et al. Fungitoxic phenols from carnation (Dianthus caryophyllus) effective against Fusarium oxysporum f. sp. dianthi. Phytochem Anal. 2003;14:8–12.

    Article  PubMed  CAS  Google Scholar 

  10. Kim J, Campbell B, Mahoney N, et al. Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs. Biochem Biophys Res Commun. 2008;372:266–71.

    Article  PubMed  CAS  Google Scholar 

  11. Kim JH, Mahoney N, Chan KL, et al. Chemosensitization of fungal pathogens to antimicrobial agents using benzo analogs. FEMS Microbiol Lett. 2008;281:64–72.

    Article  PubMed  CAS  Google Scholar 

  12. Smits GJ, Brul S. Stress tolerance in fungi—to kill a spoilage yeast. Curr Opin Biotechnol. 2005;16:225–30.

    Article  PubMed  CAS  Google Scholar 

  13. Jaeger T, Flohe L. The thiol-based redox networks of pathogens: unexploited targets in the search for new drugs. Biofactors. 2006;27:109–20.

    Article  PubMed  Google Scholar 

  14. Guillen F, Evans CS. Anisaldehyde and veratraldehyde acting as redox cycling agents for H2O2 production by Pleurotus eryngii. Appl Environ Microbiol. 1994;60:2811–7.

    PubMed  CAS  Google Scholar 

  15. Shvedova AA, Kommineni C, Jeffries BA, et al. Redox cycling of phenol induces oxidative stress in human epidermal keratinocytes. J Invest Dermatol. 2000;114:354–64.

    Article  PubMed  CAS  Google Scholar 

  16. Jacob C. A scent of therapy: pharmacological implications of natural products containing redox-active sulfur atoms. Nat Prod Rep. 2006;23:851–63.

    Article  PubMed  CAS  Google Scholar 

  17. Schwartz MA, Madhani HD. Principles of MAP kinase signaling specificity in Saccharomyces cerevisiae. Annu Rev Genet. 2004;38:725–48.

    Article  PubMed  CAS  Google Scholar 

  18. Levin DE. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2005;69:262–91.

    Article  PubMed  CAS  Google Scholar 

  19. Toone WM, Jones N. Stress-activated signalling pathways in yeast. Genes Cells. 1998;3:485–98.

    Article  PubMed  CAS  Google Scholar 

  20. Hamilton AJ, Holdom MD. Antioxidant systems in the pathogenic fungi of man and their role in virulence. Med Mycol. 1999;37:375–89.

    Article  PubMed  CAS  Google Scholar 

  21. Clemons KV, Miller TK, Selitrennikoff CP, et al. fos-1, a putative histidine kinase as a virulence factor systemic aspergillosis. Med Mycol. 2002;40:259–62.

    PubMed  CAS  Google Scholar 

  22. Campbell BC, Molyneux RJ, Schatzki TF. Current research on reducing pre- and post-harvest aflatoxin contamination of U. S. almond, pistachio and walnut. J Toxicology-Toxin Rev. 2003;22:225–66.

    CAS  Google Scholar 

  23. Food and Drug Administration (FDA). Compliance policy guides manual. Washington, DC: U.S. FDA; 1996. Sec. 555.400, 268; Sec. 570.500, 299.

  24. European Commission (EC). Commission regulation (EU) No. 165/2010 of 26 February 2010 amending regulation (EC) No. 1881/2006 setting maximum levels for certain contaminants in foodstuffs as regards aflatoxins. Off J Eur Union. 2010; L50:8–12.

  25. Gross J, Schumacher K, Schmidtberg H, et al. Protected by fumigants: beetle perfumes in antimicrobial defense. J Chem Ecol. 2008;34:179–88.

    Article  PubMed  CAS  Google Scholar 

  26. Official Methods of Analysis of AOAC INTERNATIONAL. 18th ed. Gaithersburg, MD: AOAC INTERNATIONAL; 2005. Official method 971.22.

  27. Vincent JM. Distortion of fungal hyphae in the presence of certain inhibitors. Nature. 1947;159:850.

    Article  PubMed  CAS  Google Scholar 

  28. Sekiyama Y, Mizukami Y, Takada A, et al. Effect of mustard extract vapour on fungi and spore-forming bacteria. J Antibact Antifung Agent. 1994;24:171–8.

    Google Scholar 

  29. Winzeler EA, Shoemaker DD, Astromoff A, et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science. 1999;285:901–6.

    Article  PubMed  CAS  Google Scholar 

  30. Tucker CL, Fields S. Quantitative genome-wide analysis of yeast deletion strain sensitivities to oxidative and chemical stress. Comp Funct Genomics. 2004;5:216–24.

    Article  PubMed  CAS  Google Scholar 

  31. Kim JH, Campbell BC, Yu J, et al. Examination of fungal stress response genes using Saccharomyces cerevisiae as a model system: targeting genes affecting aflatoxin biosynthesis by Aspergillus flavus Link. Appl Microbiol Biotechnol. 2005;67:807–15.

    Article  PubMed  CAS  Google Scholar 

  32. Rep M, Proft M, Remize F, et al. The Saccharomyces cerevisiae Sko1p transcription factor mediates HOG pathway-dependent osmotic regulation of a set of genes encoding enzymes implicated in protection from oxidative damage. Mol Microbiol. 2001;40:1067–83.

    Article  PubMed  CAS  Google Scholar 

  33. Ammar H, Michaelis G, Lisowsky T. A screen of yeast respiratory mutants for sensitivity against the mycotoxin citrinin identifies the vacuolar ATPase as an essential factor for the toxicity mechanism. Curr Genet. 2000;37:277–84.

    Article  PubMed  CAS  Google Scholar 

  34. Dietz KJ, Tavakoli N, Kluge C, et al. Significance of the V-type ATPase for the adaptation to stressful growth conditions and its regulation on the molecular and biochemical level. J Exp Bot. 2001;52:1969–80.

    Article  PubMed  CAS  Google Scholar 

  35. Hamilton CA, Taylor GJ, Good AG. Vacuolar H(+)-ATPase, but not mitochondrial F(1)F(0)-ATPase, is required for NaCl tolerance in Saccharomyces cerevisiae. FEMS Microbiol Lett. 2002;208:227–32.

    Article  PubMed  CAS  Google Scholar 

  36. MacDiarmid CW, Milanick MA, Eide DJ. Biochemical properties of vacuolar zinc transport systems of Saccharomyces cerevisiae. J Biol Chem. 2002;277:39187–94.

    Article  PubMed  CAS  Google Scholar 

  37. Nelson N. The vacuolar H(+)-ATPase: one of the most fundamental ion pumps in nature. J Exp Biol. 1992;172:19–27.

    PubMed  CAS  Google Scholar 

  38. Wood PM, Hollomon DW. A critical evaluation of the role of alternative oxidase in the performance of strobilurin and related fungicides acting at the Qo site of complex III. Pest Manag Sci. 2003;59:499–511.

    Article  PubMed  CAS  Google Scholar 

  39. Takimoto H, Machida K, Ueki M, et al. UK-2A, B, C and D, novel antifungal antibiotics from Streptomyces sp. 517–02. IV. Comparative studies of UK-2A with antimycin A3 on cytotoxic activity and reactive oxygen species generation in LLC-PK1 cells. J Antibiotics. 1999;52:480–4.

    CAS  Google Scholar 

Download references

Acknowledgments

This research was conducted under USDA-ARS CRIS Project 5325-42000-035-00D. We thank the Almond Board of California for partially funding this research (Agreement No. 58-5325-9-156).

Author information

Authors and Affiliations

  1. Plant Mycotoxin Research Unit, Western Regional Research Center, USDA-ARS, 800 Buchanan Street, Albany, CA, 94710, USA

    Jong H. Kim, Bruce C. Campbell, Noreen Mahoney, Kathleen L. Chan & Russell J. Molyneux

Authors
  1. Jong H. Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruce C. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noreen Mahoney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kathleen L. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Russell J. Molyneux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruce C. Campbell.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, J.H., Campbell, B.C., Mahoney, N. et al. Chemosensitization of Aflatoxigenic Fungi to Antimycin A and Strobilurin Using Salicylaldehyde, a Volatile Natural Compound Targeting Cellular Antioxidation System. Mycopathologia 171, 291–298 (2011). https://doi.org/10.1007/s11046-010-9356-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11046-010-9356-8

Keywords

Search

Navigation