Journal of Plant Diseases and Protection

, Volume 124, Issue 5, pp 413–419 | Cite as

The unpredictable risk imposed by microbial secondary metabolites: how safe is biological control of plant diseases?

  • Holger B. Deising
  • Iris Gase
  • Yasuyuki Kubo
Opinion Paper


Currently, a strong public and political demand for reducing chemical pesticides exists, supporting strengthening of biological plant protection programs in agriculture. Biological plant protection strategies largely depend on introducing antagonistic microorganisms to agro-ecosystems. This approach would indeed reduce the impact of synthetic chemistries and may help avoiding development of fungicide-resistant pathogen populations, but on the other hand may strongly increase the load of microbial toxins. In crops treated with biological control agents, neither the newly forming (confronting) microbial communities nor the secondary metabolites synthesized by these are known. Many microbial secondary metabolites may not only exhibit acute toxicities significantly exceeding those of fungicides, but even act as strong carcinogens. This paper discusses the risks imposed by the introduction of biological control agents and strongly suggests including secondary metabolite gene cluster expression data into the list of information required for approving any plant protection agents and releasing them to the field. Secondary metabolism gene expression data could strongly support assessing the risk imposed by microorganisms used in disease and pest control.


Biologics Biologicals Biological control Microbiological control agents Plant protection Secondary metabolites Toxins 



The authors thank Johannes Hallmann, Julius-Kühn-Institute for Epidemiology and Pathogen Diagnostics, Münster, Germany, Fred Klingauf, Julius-Kühn-Institute, Braunschweig, Germany, Falko Feldmann, Deutsche Phytomedizinische Gesellschaft (DPG), Braunschweig, Germany, and Axel A. Brakhage, Leibniz Institute for Natural Product Research and Infection Biology—Hans-Knöll-Institute (HKI), Jena, Germany, for critically reading and commenting on the manuscript. Research in the laboratory of H.B.D was funded by the Federal Ministry of Education and Research (BMBF; AZ 031A353A) and the German Research Foundation (DFG; DE 403/18-1).


  1. Anke T, Oberwinkler F, Steglich W, Schramm G (1977) The strobilurins—new antifungal antibiotics from the basidiomycete Strobilurus tenacellus. J Antibiot 30:806–810CrossRefPubMedGoogle Scholar
  2. Barkai-Golan R, Paster N (eds) (2008) Mycotoxins in fruits and vegetables. Elsevier Inc., San DiegoGoogle Scholar
  3. Bartlett DW, Clough JM, Godwin JR, Hall AA, Hamer M, Parr-Dobrzanski B (2002) The strobilurin fungicides. Pest Manag Sci 58:649–662CrossRefPubMedGoogle Scholar
  4. Becher R, Hettwer U, Karlovsky P, Deising HB, Wirsel SGR (2010) Adaptation of Fusarium graminearum to tebuconazole yielded descendants diverging for levels of fitness, fungicide resistance, virulence, and mycotoxin production. Phytopathology 100:444–453CrossRefPubMedGoogle Scholar
  5. Bitz S (2010) The Botulinum neurotoxin LD50 test—problems and solutions. Altex 27:114–116CrossRefPubMedGoogle Scholar
  6. Boyd EM, Shanas MN (1963) The acute oral toxicity of sodium chloride. Arch Int Pharmacodyn Thér 144:86–96PubMedGoogle Scholar
  7. Brakhage AA (2013) Regulation of fungal secondary metabolism. Nat Rev Microbiol 11:21–32CrossRefPubMedGoogle Scholar
  8. Brakhage AA, Schuemann J, Bergmann S, Scherlach K, Schroeckh V, Hertweck C (2008) Activation of fungal silent gene clusters: a new avenue to drug discovery. In: Petersen F, Amstutz R (eds) Natural compounds as drugs. Birkhäuser, Basel, pp 1–12Google Scholar
  9. Cameron GR, Cheng K-K (1951) Failure of oral D.D.T. to induce toxic changes in rats. Br Med J 2:819–821CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chang FJ, Syrjanen S, Wang LJ, Syrjanen K (1992) Infectious agents in the etiology of esophageal cancer. Gastroenterology 103:1336–1348CrossRefPubMedGoogle Scholar
  11. Chu FS, Li GY (1994) Simultaneous occurrence of fumonisin B1 and other mycotoxins in moldy corn collected from the People’s Republic of China in regions with high incidences of esophageal cancer. Appl Environ Microbiol 60:847–852PubMedPubMedCentralGoogle Scholar
  12. Cuomo CA, Güldener U, Xu JR, Trail F, Turgeon BG, Di Pietro A, Walton JD, Ma LJ, Baker SE, Rep M, Adam G, Antoniw J, Baldwin T, Calvo S, Chang YL, Decaprio D, Gale LR, Gnerre S, Goswami RS, Hammond-Kosack K, Harris LJ, Hilburn K, Kennell JC, Kroken S, Magnuson JK, Mannhaupt G, Mauceli E, Mewes HW, Mitterbauer R, Muehlbauer G, Münsterkötter M, Nelson D, O’Donnell K, Ouellet T, Qi W, Quesneville H, Roncero MI, Seong KY, Tetko IV, Urban M, Waalwijk C, Ward TJ, Yao J, Birren BW, Kistler HC (2007) The Fusarium graminearum genome reveals a link between localized polymorphism and pathogen specialization. Science 317:1400–1402CrossRefPubMedGoogle Scholar
  13. Deising HB, Werner S, Wernitz M (2000) The role of fungal appressoria in plant infection. Microbes Infect 2:1631–1641CrossRefPubMedGoogle Scholar
  14. Deising HB, Fraaije B, Mehl A, Oerke EC, Stammler G (eds) (2017) Modern fungicides and antifungal compounds VIII. DPG-Verlag, BraunschweigGoogle Scholar
  15. Dhanasekaran D, Shanmugapriya S, Thajuddin N, Panneerselvam A (2011) Aflatoxins and aflatoxicosis in human and animals. In: Guevara-Gonzalez RG (ed) Aflatoxins—biochemistry and molecular biology. InTechOpen, Rijeka, pp 221–254Google Scholar
  16. Ellner FM (2005) Results of long-term field studies into the effect of strobilurin containing fungicides on the production of mycotoxins in several winter wheat varieties. Mycotoxin Res 21:112–115CrossRefPubMedGoogle Scholar
  17. Fisch KM, Gillaspy AF, Gipson M, Henrikson JC, Hoover AR, Jackson L, Najar FZ, Wägele H, Cichewicz RH (2009) Chemical induction of silent biosynthetic pathway transcription in Aspergillus niger. J Ind Microbiol Biotechnol 36:1199–1213CrossRefPubMedGoogle Scholar
  18. Haarmann T, Rolke Y, Giesbert S, Tudzynski P (2009) Ergot: from witchcraft to biotechnology. Mol Plant Pathol 10:563–577CrossRefPubMedGoogle Scholar
  19. Hayes AW, Phillips TD, Williams WL, Ciegler A (1979) Acute toxicity of patulin in mice and rats. Toxicology 13:91–100PubMedGoogle Scholar
  20. He X-Y, Tang L, Wang S-L, Cai Q-S, Wang J-S, Hong J-Y (2006) Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. Int J Cancer 118:2665–2671CrossRefPubMedGoogle Scholar
  21. Izawa M, Takekawa O, Arie T, Teraoka T, Yoshida M, Kimura M, Kamakura T (2009) Inhibition of histone deacetylase causes reduction of appressorium formation in the rice blast fungus Magnaporthe oryzae. J Gen Appl Microbiol 55:489–498CrossRefPubMedGoogle Scholar
  22. Kalantari H, Moosavi M (2010) Review on T-2 toxin. Jund J Nat Pharm Prod 5:26–38Google Scholar
  23. Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND (2010) SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol 47:736–741CrossRefPubMedPubMedCentralGoogle Scholar
  24. Kubo Y, Furusawa I (1986) Localization of melanin in appressoria of Colletotrichum lagenarium. Can J Microbiol 32:280–282CrossRefGoogle Scholar
  25. Kubo Y, Furusawa I (1991) Melanin biosynthesis. Prerequisite for successful invasion of the host by appressoria of Colletotrichum and Pyricularia. In: Cole GT, Hoch HC (eds) The fungal spore and disease initiation in plants and animals. Plenum Publishing Corporation, New York, pp 205–218CrossRefGoogle Scholar
  26. Kubo Y, Suzuki K, Furusawa I, Yamamoto M (1982) Effect of Tricyclazole on appressorial pigmentation and penetration from appressoria of Colletotrichum lagenarium. Phytopathology 72:1198–1200CrossRefGoogle Scholar
  27. Kubo Y, Suzuki K, Furusawa I, Yamamoto M (1983) Scytalone as a natural intermediate of melanin biosynthesis in appressoria of Colletotrichum lagenarium. Exp Mycol 7:208–215CrossRefGoogle Scholar
  28. Kubo Y, Takano Y, Endo N, Yasuda N, Tajima S, Furusawa I (1996) Cloning and structural analysis of the melanin biosynthesis gene SCD1 encoding scytalone dehydratase in Colletotrichum lagenarium. Appl Environ Microbiol 62:4340–4344PubMedPubMedCentralGoogle Scholar
  29. Kulik T, Łojko M, Jestoi M, Perkowski J (2012) Sublethal concentrations of azoles induce tri transcript levels and trichothecene production in Fusarium graminearum. FEMS Microbiol Lett 335:58–67CrossRefPubMedGoogle Scholar
  30. Lindow SE, Brandl MT (2003) Microbiology of the phyllosphere. Appl Environ Microbiol 69:1875–1883CrossRefPubMedPubMedCentralGoogle Scholar
  31. Ludwig N, Löhrer M, Hempel M, Mathea S, Schliebner I, Menzel M, Kiesow A, Schaffrath U, Deising HB, Horbach R (2014) Melanin is not required for turgor generation but enhances cell wall rigidity in appressoria of the corn pathogen Colletotrichum graminicola. Mol Plant-Microbe Interact 27:315–327CrossRefPubMedGoogle Scholar
  32. Luo Y, Yoshizawa T, Katayama T (1990) Comparative study on the natural occurrence of Fusarium mycotoxins (trichothecenes and zearalenone) in corn and wheat from high-risk and low-risk areas for human esophageal cancer in China. Appl Environ Microbiol 56:3723–3726PubMedPubMedCentralGoogle Scholar
  33. Macheleidt J, Mattern DJ, Fischer J, Netzker T, Weber J, Schroeckh V, Valiante V, Brakhage AA (2016) Regulation and role of fungal secondary metabolites. Annu Rev Genet 50:371–392CrossRefPubMedGoogle Scholar
  34. Netzker T, Fischer J, Weber J, Mattern DJ, König CC, Valiante V, Schroeckh V, Brakhage AA (2015) Microbial communication leading to the activation of silent fungal secondary metabolite gene clusters. Front Microbiol 6:299CrossRefPubMedPubMedCentralGoogle Scholar
  35. Norppa H, Penttila M, Sorsa M, Hintikka E-L, Ilus T (1980) Brief report mycotoxin T-2 of Fusarium tricinctum and chromosome changes in Chinese hamster bone marrow. Hereditas 93:329–332CrossRefPubMedGoogle Scholar
  36. Paranjape K, Gowariker V, Krishnamurthy VN, Gowariker S (eds) (2015) The pesticide encyclopedia. CAB International, WallingfordGoogle Scholar
  37. Pasquet J, Mazuret A, Fournel J, Koenig FH (1976) Acute oral and percutaneous toxicity of phosalone in the rat, in comparison with azinphosmethyl and parathion Toxicol. Appl Pharmacol 37:85–92CrossRefGoogle Scholar
  38. Perger G, Szadkowski D (1994) Toxicology of pyrethroids and their relevance to human health. Ann Agric Environ Med 1:11–17Google Scholar
  39. Perlman D (ed) (1977) Advances in Applied Microbiology. Academic Press, New YorkGoogle Scholar
  40. Ponts N (2015) Mycotoxins are a component of Fusarium graminearum stress-response system. Front Microbiol 6:1234CrossRefPubMedPubMedCentralGoogle Scholar
  41. Pottenger LH, Andrews LS, Bachman AN, Boogaard PJ, Cadet J, Embry MR, Farmer PB, Himmelstein MW, Jarabek AM, Martin EA, Mauthe RJ, Persaud R, Preston RJ, Schoeny R, Skare J, Swenberg JA, Williams GM, Zeiger E, Zhang F, Kim JH (2014) An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. Crit Rev Toxicol 44:348–391CrossRefPubMedGoogle Scholar
  42. Purchase IFH, Theron JJ (1968) The acute toxicity of ochratoxin A to rats. Food Cosmet Toxicol 6:479–480CrossRefPubMedGoogle Scholar
  43. Rank C, Larsen T, Frisvad J (2010) Functional systems biology of Aspergillus. In: Machida M, Gomi K (eds) Aspergillus: molecular biology and genomics. Academic Press, Wymondham, pp 173–198Google Scholar
  44. Rees KR (1966) Plant toxins and human disease. The mechanism of action of aflatoxin in producing acute liver necrosis. Proc R Soc Med 59:755–757PubMedPubMedCentralGoogle Scholar
  45. Sbaraini N, Guedes RLM, Andreis FC, Junges Â, de Morais GL, Vainstein MH, de Vasconcelos ATR, Schrank A (2016) Secondary metabolite gene clusters in the entomopathogen fungus Metarhizium anisopliae: genome identification and patterns of expression in a cuticle infection model. BMC Genomics 17(8):736CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sheets LP, Li AA, Minnema DJ, Collier RH, Creek MR, Peffer RC (2016) A critical review of neonicotinoid insecticides for developmental neurotoxicity. Crit Rev Toxicol 46:153–190CrossRefPubMedGoogle Scholar
  47. Vanhaecke T, Papeleu P, Elaut G, Rogers V (2004) Trichostatin A-likehydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view. Curr Med Chem 11:1629–1643CrossRefPubMedGoogle Scholar
  48. Vorholt JA (2012) Microbial life in the phyllosphere. Nat Rev Microbiol 10:828–840CrossRefPubMedGoogle Scholar
  49. Wiberg GS, Trenholm HL, Coldwell BB (1970) Increased ethanol toxicity in old rats: changes in LD50, in vivo and in vitro metabolism, and liver alcohol dehydrogenase activity. Toxicol Appl Pharmacol 16:718–727CrossRefPubMedGoogle Scholar
  50. Xiao G, Ying S-H, Zheng P, Wang Z-L, Zhang S, Xie X-Q, Shang Y, St. Leger RJ, Zhao G-P, Wang C, Feng M-G (2012) Genomic perspectives on the evolution of fungal entomopathogenicity in Beauveria bassiana. Sci Rep 2:483CrossRefPubMedPubMedCentralGoogle Scholar
  51. Yazar S, Omurtag GZ (2008) Fumonisins, trichothecenes and zearalenone in cereals. Int J Mol Sci 9:2062–2090CrossRefPubMedPubMedCentralGoogle Scholar
  52. Zeilinger S, Gruber S, Bansal R, Mukherjee PK (2016) Secondary metabolism in Trichoderma–Chemistry meets genomics. Fungal Biol Rev 30:74–90CrossRefGoogle Scholar

Copyright information

© Deutsche Phythomedizinische Gesellschaft 2017

Authors and Affiliations

  1. 1.Chair of Phytopathology and Plant Protection, Institute for Agricultural and Nutritional Sciences, Faculty of Natural Sciences IIIMartin-Luther-University Halle-WittenbergHalle (Saale)Germany
  2. 2.Laboratory of Plant Pathology, Graduate School of Life and Environmental SciencesKyoto Prefectural UniversityKyotoJapan

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