Fumigaclavines D–H, New Ergot Alkaloids from Endophytic Aspergillus fumigatus

Abstract

Ergot alkaloids are toxins which are produced biotechnologically on an industrial scale. The chemical investigation of endophytic Aspergillus fumigatus resulted in the isolation of five new ergot alkaloids named fumigaclavines D–H (2–6), along with three known analogues, fumigaclavine C (1), festuclavine (7), and fumigaclavine A (8). Their structures were unequivocally elucidated by extensive spectroscopic analyses in association with X-ray single-crystal diffraction. Fumigaclavines D–H are interesting clavine-type ergot alkaloids featuring a reverse prenyl moiety at C-2, with 1–4, 6, and 8 bearing additional substituents, e.g., an OH or OAc group at C-9. Compounds 2, 4, and 6–8 showed a broad spectrum of antimicrobial activity against a panel of anaerobic microorganisms, of which compounds 4 and 6 were the most active against Veillonella parvula with an MIC = 16 µg/mL compared to that (0.12 µg/mL) of tinidazole, co-assayed as a positive reference.

Key words

Aspergillus fumigates - Trichocomaceae - Cynodon dactylon - Poaceae - clavine-type ergot alkaloids - antimicrobial activity

• References

• 1 Tan RX, Zou WX. Endophytes: a rich source of functional metabolites. Nat Prod Rep 2001; 18: 448-459
• 2 Xu J, Ebada SS, Proksch P. Chemistry and bioactivity of natural products from the fungal genus Pestalotiopsis . Fungal Divers 2010; 44: 15-31
• 3 Xu J. Biomolecules produced by mangrove-associated microbes. Curr Med Chem 2011; 18: 5224-5266
• 4 Gugnani HC. Ecology and taxonomy of pathogenic Aspergilli . Frontiers Biosci 2003; 8: 346-357
• 5 Frisvad JC, Kristian FN, Thomas OL. Metabolomics of Aspergillus fumigatus. Med Mycol 2008; 47: S53-S71
• 6 Liu X, Wang L, Steffan N, Yin WB, Li SM. Ergot alkaloid biosynthesis in Aspergillus fumigatus: FgaAT catalyses the acetylation of fumigaclavine B. Chembiochem 2009; 10: 2325-2328
• 7 Matuschek M, Wallwey C, Xie XL, Li SM. New insights into ergot alkaloid biosynthesis in Claviceps purpurea: an agroclavine synthase EasG catalyses, via a non-enzymatic adduct with reduced glutathione, the conversion of chanoclavine-I aldehyde to agroclavine. Org Biomol Chem 2011; 9: 4328-4335
• 8 Clardy J, Fischbach MA, Walsh CT. New antibiotics from bacterial natural products. Nat Biotechnol 2006; 24: 1541-1550
• 9 Xu J, Kjer J, Sendker J, Wray V, Guan HS, Edrada RA, Müller WEG, Bayer M, Lin WH, Wu J, Proksch P. Cytosporones, coumarins, and an alkaloid from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata . Bioorg Med Chem 2009; 17: 7362-7367
• 10 Xu J, Kjer J, Sendker J, Wray V, Guan HS, Edrada RA, Lin WH, Wu J, Proksch P. Chromones from the endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata . J Nat Prod 2009; 72: 662-665
• 11 Xu J, Lin Q, Wang B, Wray V, Lin WH, Proksch P. Pestalotiopamide E, a new amide from endophytic fungus Pestalotiopsis sp. J Asian Nat Prod Res 2011; 13: 373-376
• 12 Xu J, Aly AH, Wray V, Proksch P. Polyketide derivatives of endophytic fungus Pestalotiopsis sp. isolated from the Chinese mangrove plant Rhizophora mucronata . Tetrahedron Lett 2011; 52: 21-25
• 13 Hemberger Y, Xu J, Wray V, Proksch P, Wu J, Bringmann G. Pestalotiopens A and B: stereochemically challenging flexible sesquiterpene-cyclopaldic acid hybrids from Pestalotiopsis sp. Chem Eur J 2013; 19: 15556-15564
• 14 Liu JY, Song YC, Zhang Z, Wang L, Guo ZJ, Zou WX, Tan RX. Aspergillus fumigatus CY018, an endophytic fungus in Cynodon dactylon as a versatile producer of new and bioactive metabolites. J Biotechnol 2004; 114: 279-287
• 15 Ge HM, Yu ZG, Zhang J, Wu JH, Tan RX. Bioactive alkaloids from endophytic Aspergillus fumigatus . J Nat Prod 2009; 72: 753-755
• 16 Cole RJ, Kirksey JW, Dorner JW, Wilson DM, Johnson JC, Johnson JA, Bedell DM, Springer JP, Chexal KK. Mycotoxins produced by Aspergillus fumigatus species isolated from molded silage. J Agric Food Chem 1977; 25: 826-830
• 17 Wallwey C, Li SM. Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat Prod Rep 2011; 28: 496-510
• 18 Di Modugno E, Erbetti I, Ferrari L, Galassi G, Hammond SM, Xerri L. In vitro activity of the tribactam GV104326 against gram-positive, gram-negative, and anaerobic bacteria. Antimicrob Agents Chemother 1994; 38: 2362-2368
• 19 Rankin ID. MIC testing. In: Coyle MB, editor Manual of antimicrobial susceptibility testing. Washington: University of Washington; 2005: 53-62
• 20 Bach NJ, Boaz HE, Kornfeld EC, Chang CJ, Floss HG, Hagaman EW, Wenkert E. Carbon-13 nuclear magnetic resonance spectroscopy of naturally occurring substances. XXI. Nuclear magnetic resonance spectral analysis of the ergot alkaloids. J Org Chem 1974; 39: 1272-1276