Skip to main content
SpringerLink
Log in

Diversity and bioactivity of Armillaria sesquiterpene aryl ester natural products

Mycological Progress volume 18, pages 1027–1037 (2019)Cite this article

Abstract

Species of the basidiomycete genus Armillaria produce bioactive small molecule natural products, referred to as melleolides. With more than 70 described members, this class of natural products is a prime example for diversity-oriented biosynthesis. Chemically, they represent hybrid molecules, composed of a tricyclic, chiral sesquiterpene protoilludene alcohol, esterified with the tetraketide orsellinic acid or its derivatives. In this review article, we summarize the melleolide’s structural diversity and present—to the extent elucidated—the enzymatic basis how their backbone structures are biosynthesized and modified. We also highlight the current knowledge on their antimicrobial, phytotoxic, and cytotoxic bioactivities, along with a view on the molecular targets of the melleolides, their unparalleled structure-activity relationships, and their modes of action.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  • Abraham WR (2001) Bioactive sesquiterpenes produced by fungi: are they useful for humans as well? Curr Med Chem 8:583–606

    Article  CAS  PubMed  Google Scholar 

  • Arnone A, Cardillo R, Nasini G (1986) Structures of melleolides B-D, three antibacterial sesquiterpenoids from Armillaria mellea. Phytochemistry 25:471–474

    Article  CAS  Google Scholar 

  • Arnone A, Cardillo R, Nasini G (1988a) Isolation and structure elucidation of melleolides I and J and armellides A and B, novel sesquiterpenoid aryl esters from Armillaria novae-zelandiae. Gazz Chim Ital 118:523–527

    CAS  Google Scholar 

  • Arnone A, Cardillo R, Nasini G (1988b) Secondary mould metabolites part 19: structure elucidation and absolute configuration of melledonals B and C, novel antibacterial sesquiterpenoids from Armillaria mellea. X-ray molecular structure of Melledonal C. J Chem Soc Perkin Trans 1 I:503–510

    Article  Google Scholar 

  • Arnone A, Nasini G, Di Modugno V, Cardillo R (1988c) Isolation and structure elucidation of melledonals D and E and melleolides E-H, novel sesquiterpenoid aryl esters from Clitocybe elegans and Armillaria mellea. Gazz Chim Ital 118:517–521

    CAS  Google Scholar 

  • Baumgartner K, Coetzee MP, Hoffmeister D (2011) Secrets of the subterranean pathosystem of Armillaria. Mol Plant Pathol 12:515–534

    Article  PubMed  PubMed Central  Google Scholar 

  • Bohnert M, Miethbauer S, Dahse HM, Ziemen J, Nett M, Hoffmeister D (2011) In vitro cytotoxicity of melleolide antibiotics: structural and mechanistic aspects. Bioorg Med Chem Lett 21:2003–2006

    Article  CAS  PubMed  Google Scholar 

  • Bohnert M, Nützmann HW, Schroeckh V, Horn F, Dahse HM, Brakhage AA, Hoffmeister D (2014a) Cytotoxic and antifungal activities of melleolide antibiotics follow dissimilar structure–activity relationships. Phytochemistry 105:101–108

    Article  CAS  PubMed  Google Scholar 

  • Bohnert M, Scherer O, Wiechmann K, König S, Dahse HM, Hoffmeister D, Werz O (2014b) Melleolides induce rapid cell death in human primary monocytes and cancer cells. Bioorg Med Chem 22:3856–3861

    Article  CAS  PubMed  Google Scholar 

  • Braesel J, Fricke J, Schwenk D, Hoffmeister D (2017) Biochemical and genetic basis of orsellinic acid biosynthesis and prenylation in a stereaceous basidiomycete. Fungal Genet Biol 98:12–19

    Article  CAS  PubMed  Google Scholar 

  • Brazee NJ, Ortiz-Santana B, Banik MT, Lindner DL (2012) Armillaria altimontana, a new species from the western interior of North America. Mycologia 104:1200–1205

    Article  PubMed  Google Scholar 

  • Chen CC, Kuo YH, Cheng JJ, Sung PJ, Ni CL, Chen CC, Shen CC (2015) Three new sesquiterpene aryl esters from the mycelium of Armillaria mellea. Molecules 20:9994–10003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Collins C, Keane TM, Turner DJ, O’Keeffe G, Fitzpatrick DA, Doyle S (2013) Genomic and proteomic dissection of the ubiquitous plant pathogen, Armillaria mellea: toward a new infection model system. J Proteome Res 12:2552–2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cremin P, Donnelly DMX, Wolfender JL, Hostettmann K (1995) Liquid chromatography–thermospray mass spectrometric analysis of sesquiterpenes of Armillaria (Eumycota: Basidiomycotina) species. J Chromatogr A 710:273–285

    Article  CAS  Google Scholar 

  • Cremin P, Guiry PJ, Wolfender JL, Hostettmann K, Donnelly DMX (2000) A liquid chromatography–thermospray ionisation–mass spectrometry guided isolation of a new sesquiterpene aryl ester from Armillaria novae-zelandiae. J Chem Soc Perkin Trans 1:2325–2329

    Article  Google Scholar 

  • Donnelly DMX, Sanada S, O’Reilly J, Polonsky J, Prangé T, Pascard CJ (1982) Isolation and structure (X-ray analysis) of the orsellinate of armillol, a new antibacterial metabolite from Armillaria mellea. J Chem Soc Chem Comm 135–137

  • Donnelly DMX, Polonsky J, Prangé T, Snatzke, G, Wagner U (1984) The absolute configuration of the orsellinate of armillol; application of the coupled oscillator theory. J Chem Soc Chem Comm 222–223

  • Donnelly DMX, Abe F, Coveney D, Fukuda N, O’Reilly J, Polonsky J, Prangé T (1985a) Antibacterial sesquiterpene aryl esters from Armillaria mellea. J Nat Prod 48:10–16

    Article  CAS  PubMed  Google Scholar 

  • Donnelly DMX, Coveney DJ, Polonsky J (1985b) Melledonal and melledonol, sesquiterpene esters from Armillaria mellea. Tetrahedron Lett 26:5343–5344

    Article  CAS  Google Scholar 

  • Donnelly DMX, Coveney DJ, Fukuda N, Polonsky J (1986) New sesquiterpene aryl esters from Armillaria mellea. J Nat Prod 49:111–116

    Article  CAS  Google Scholar 

  • Donnelly DMX, Coveney DJ (1987) Antibacterial sesquiterpene aryl esters from Armillaria mellea. In: Hostettmann K, Lea PJ (eds) Biologically active natural products. Clarendon Press, Oxford, pp 19–32

    Google Scholar 

  • Donnelly DMX, Quigley PF, Coveney DJ, Polonsky J (1987) Two new sesquiterpene esters from Armillaria mellea. Phytochemistry 26:3075–3077

    Article  CAS  Google Scholar 

  • Donnelly DMX, Hutchinson RM (1990) Armillane, a saturated sesquiterpene ester from Armillaria mellea. Phytochemistry 29:179–182

    Article  CAS  Google Scholar 

  • Donnelly DMX, Hutchinson RM, Coveney DJ, Yonemitsu M (1990) Sesquiterpene aryl esters from Armillaria mellea. Phytochemistry 29:2569–2572

    Article  CAS  Google Scholar 

  • Donnelly DMX, Konishi T, Dunne O, Cremin P (1997) Sesquiterpene aryl esters from Armillaria tabescens. Phytochemistry 44:1473–1478

    Article  CAS  Google Scholar 

  • Dörfer M, Heine D, König S, Gore S, Werz O, Hertweck C, Gressler M, Hoffmeister D (2019) Melleolides impact fungal translation via Elongation Factor 2. Org Biomol Chem 17:4906–4916

    Article  PubMed  Google Scholar 

  • Engels B, Heinig U, Grothe T, Stadler M, Jennewein S (2011) Cloning and characterization of an Armillaria gallica cDNA encoding protoilludene synthase, which catalyzes the first committed step in the synthesis of antimicrobial melleolides. J Biol Chem 286:6871–6878

    Article  CAS  PubMed  Google Scholar 

  • Engels B (2013) Untersuchungen zur Biosynthese sesquiterpenoider Naturstoffe, der Melleolide. In Armillaria gallica. Dissertation, RWTH Aachen

  • Firn RD, Jones GC (2003) Natural products – a simple model to explain chemical diversity. Nat Prod Rep 20:382–391

    Article  CAS  PubMed  Google Scholar 

  • Firn RD, Jones GC (2009) A Darwinian view of metabolism: molecular properties determine fitness. J Exp Bot 60:719–726

    Article  CAS  PubMed  Google Scholar 

  • Gill M, Steglich W (1987) Pigments of fungi (Macromycetes). Prog Chem Org Nat Prod 51:1–317

    CAS  Google Scholar 

  • Gill M (2003) Pigments of fungi (Macromycetes). Nat Prod Rep 20:615–639

    Article  CAS  PubMed  Google Scholar 

  • Hovey MT, Cohen DT, Walden DM, Cheong PH, Scheidt KA (2017) A carbene catalysis strategy for the synthesis of protoilludane natural products. Angew Chem Int Ed 56:9864–9867

    Article  CAS  Google Scholar 

  • Jiang MY, Feng T, Liu JK (2011) N-containing compounds of macromycetes. Nat Prod Rep 28:783–808

    Article  CAS  PubMed  Google Scholar 

  • Kobori H, Sekiya A, Suzuki T, Choi JH, Hirai H, Kawagishi H (2015) Bioactive sesquiterpene aryl esters from the culture broth of Armillaria sp. J Nat Prod 78:163–167

    Article  CAS  PubMed  Google Scholar 

  • Koch RA, Wilson AW, Séné O, Henkel TW, Aime MC (2017) Resolved phylogeny and biogeography of the root pathogen Armillaria and its gasteroid relative, Guyanagaster. BMC Evol Biol 17:33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • König S, Romp E, Krauth V, Rühl M, Dörfer M, Liening S, Hofmann B, Häfner AK, Steinhilber D, Karas M, Garscha U, Hoffmeister D, Werz O (2019) Melleolides from honey mushroom inhibit 5-lipoxygenase via Cys159. Cell Chem Biol 26:60–70

    Article  CAS  PubMed  Google Scholar 

  • Lackner G, Bohnert M, Wick J, Hoffmeister D (2013) Assembly of melleolide antibiotics involves a polyketide synthase with cross-coupling activity. Chem Biol 20:1101–1106

    Article  CAS  PubMed  Google Scholar 

  • Li Z, Wang Y, Jiang B, Li W, Zheng L, Yang X, Bao Y, Sun L, Huang Y, Li Y (2016) Structure, cytotoxic activity and mechanism of protoilludane sesquiterpene aryl esters from the mycelium of Armillaria mellea. J Ethnopharmacol 184:119–127

    Article  CAS  PubMed  Google Scholar 

  • McMorris TC, Nair MSR, Anchel M (1967) The structure of illudol, a sesquiterpenoid triol from Clitocybe illudens. J Am Chem Soc 89:4562–4563

    Article  CAS  PubMed  Google Scholar 

  • Midland SL, Izac RR, Wing RM, Zaki AL, Munnecke DE, Sims JJ (1982) Melleolide, a new antibiotic from Armillaria mellea. Tetrahedron Lett 23:2515–2518

    Article  CAS  Google Scholar 

  • Misiek M, Williams J, Schmich K, Hüttel W, Merfort I, Salomon CE, Aldrich CC, Hoffmeister D (2009) Structure and cytotoxicity of arnamial and related fungal sesquiterpene aryl esters. J Nat Prod 72:1888–1891

    Article  CAS  PubMed  Google Scholar 

  • Misiek M, Braesel J, Hoffmeister D (2011) Characterization of the ArmA adenylation domain implies a more diverse secondary metabolism in the genus Armillaria. Fungal Biol 115:775–781

    Article  CAS  PubMed  Google Scholar 

  • Misiek M, Hoffmeister D (2012) Sesquiterpene aryl ester natural products in North American Armillaria species. Mycol Prog 11:7–15

    Article  Google Scholar 

  • Momose I, Sekizawa R, Hosokawa N, Iinuma H, Matsui S, Nakamura H, Naganawa H, Hamada M, Takeuchi T (2000) Melleolides K, L and M, new melleolides from Armillariella mellea. J Antibiot 53:137–143

    Article  CAS  PubMed  Google Scholar 

  • Obuchi T, Kondoh H, Watanabe N, Tamai M, Omura S, Yang JS, Liang XT (1990) Armillaric acid, a new antibiotic produced by Armillaria mellea. Planta Med 56:198–201

    Article  CAS  PubMed  Google Scholar 

  • Oduro KA, Munnecke DE, Sims JJ, Keen NT (1976) Isolation of antibiotics produced in culture by Armillaria mellea. Trans Br Mycol Soc 66:195–199

    Article  Google Scholar 

  • Oppermann A (1951) Das antibiotische Verhalten einiger holzzersetzender Basidiomyceten zueinander und zu Bakterien. Arch Mikrobiol 16:364–409

    Article  Google Scholar 

  • Peipp H, Sonnenbichler J (1992) Secondary fungal metabolites and their biological activities, II. Occurrence of antibiotic compounds in cultures of Armillaria ostoyae growing in the presence of an antagonistic fungus or host plant cells. Biol Chem Hoppe Seyler 373:675–683

    Article  CAS  PubMed  Google Scholar 

  • Sandargo B, Chepkirui C, Cheng T, Chaverra-Munoz L, Thongbai B, Stadler M, Hüttel S (2019) Biological and chemical diversity go hand in hand: Basidiomycota as source of new pharmaceuticals and agrochemicals. Biotechnol Adv. https://doi.org/10.1016/j.biotechadv.2019.01.011

  • Schroeckh V, Scherlach K, Nützmann HW, Shelest E, Schmidt-Heck W, Schümann J, Martin K, Hertweck C, Brakhage AA (2009) Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A 106:14558–14563

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen B (2003) Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr Opin Chem Biol 7:285–295

    Article  CAS  PubMed  Google Scholar 

  • Sonnenbichler J, Guillaumin JJ, Peipp H, Schwarz D (1997) Secondary metabolites from dual cultures of genetically different Armillaria isolates. Eur J Forest Path 27:241–249

    Article  Google Scholar 

  • Wang C, Guo S, Chen X, Ca W, Xu J, Xiao P (1996) Studies on the contents of armillarin and melleolide at different stages of development of Armillaria mellea. Zhongguo Zhong Yao Za Zhi 21:274–276

    CAS  PubMed  Google Scholar 

  • Wick J, Heine D, Lackner G, Misiek M, Tauber J, Jagusch H, Hertweck C, Hoffmeister D (2016) A fivefold parallelized biosynthetic process secures chlorination of Armillaria mellea (honey mushroom) toxins. Appl Environ Microbiol 82:1196–1204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamazaki M, Matsuo M, Shibata S (1965) Biosynthesis of lichen depsides, lecanoric acid and atranorin. Chem Pharm Bull 13:1015–1017

    Article  CAS  PubMed  Google Scholar 

  • Yang JS, Chen Y, Feng X, Yu D, Liang X (1984) Chemical constituents of Armillaria mellea mycelium I. Isolation and characterization of armillarin and armillaridin. Planta Med 50:288–290

    Article  CAS  PubMed  Google Scholar 

  • Yang JS, Cong PZ (1988) Mass spectrometric studies on the sesquiterpenol aromatic esters from mycelium of Armillaria mellea. Acta Chim Sin 46:1093–1100

    CAS  Google Scholar 

  • Yang JS, Chen YW, Zeng XZ, Yu DQ, He CH, Zheng QT, Yang J, Liang XT (1989a) Isolation and structure elucidation of armillaricin. Planta Med 55:564–565

    Article  CAS  PubMed  Google Scholar 

  • Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Cong PZ, Tamai M, Obuchi T, Kondoh H, Liang XT (1989b) Isolation and structures of two new sesquiterpenoid aromatic esters: armillarigin and armillarikin. Planta Med 55:479–481

    Article  CAS  PubMed  Google Scholar 

  • Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT, He CH, Zheng QT, Yang JJ, Yang J (1990a) Chemical constituents of Armillaria mellea mycelium VI. Isolation and structure of armillaripin. Acta Pharm Sin 25:353–356

    CAS  Google Scholar 

  • Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1990b) Studies on the chemical constituents of Armillaria mellea mycelium V. Isolation and characterization of armillarin and armillarinin. Acta Pharm Sin 24:24–28

    Google Scholar 

  • Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1991a) Chemical constituents of Armillaria mellea mycelium VII. Isolation and characterization of chemical constituents of the acetone extract. Acta Pharm Sin 26:117–122

    CAS  Google Scholar 

  • Yang JS, Su YL, Wang YL, Feng XZ, Yu DQ, Liang XT (1991b) Two novel protoilludane norsesquiterpenoid esters, armillasin and armillatin from Armillaria mellea. Planta Med 57:478–480

    Article  CAS  PubMed  Google Scholar 

  • Yang JS, Su YL, Yu DQ, Liang XT (1993) Carbon-13 nuclear magnetic resonance spectra of some protoilludane sesquiterpenoid aromatic esters from Armillaria mellea. J Chin Pharm Sci 2:11–17

    CAS  Google Scholar 

  • Zhou ZY, Liu JK (2010) Pigments of fungi (macromycetes). Nat Prod Rep 27:1531–1570

    Article  CAS  PubMed  Google Scholar 

  • Zjawiony JK (2004) Biologically active compounds from Aphyllophorales (polypore) fungi. J Nat Prod 67:300–310

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Studies on melleolide biosynthesis and mode of action in D.H.’s laboratory were supported by the Excellence Graduate School JSMC (Jena School for Microbial Communication) and by the Collaborative Research Center ChemBioSys (Deutsche Forschungsgemeinschaft, grant SFB1127).

Author information

Authors and Affiliations

  1. Department Pharmaceutical Microbiology at the Hans-Knöll-Institute, Friedrich-Schiller-Universität, Winzerlaer Strasse 2, 07745, Jena, Germany

    Maximilian Dörfer, Markus Gressler & Dirk Hoffmeister

Authors
  1. Maximilian Dörfer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Gressler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dirk Hoffmeister
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dirk Hoffmeister.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Responsible editor: Marc Stadler

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the “Topic collection on Basidiomycote Mycology in honor of Franz Oberwinkler who passed away in March 2018.”

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dörfer, M., Gressler, M. & Hoffmeister, D. Diversity and bioactivity of Armillaria sesquiterpene aryl ester natural products. Mycol Progress 18, 1027–1037 (2019). https://doi.org/10.1007/s11557-019-01508-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11557-019-01508-z

Keywords

search

Navigation