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Occurrence of cyclosporins and cyclosporin-like peptolides in fungi

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Journal of Industrial Microbiology

Abstract

Apart from 17 previously listed fungal taxa producing cyclosporin A and its natural congeners B to Z, several additional and taxonomically diverse strains producing the single novel component [Thr2, Leu5, Leu10]cyclosporin or cyclosporin-like peptolides (eg SDZ 214-103=[Thr2, Leu5, D-Hiv8, Leu10]cyclosporin) have recently been described. We report here the isolation of two further and novel cyclosporins, [Thr2, Leu5, Ala10]cyclosporin (2) and [Thr2, Ile5] cyclosporin (3), from strains classified asAcremonium luzulae (Fuckel) W Gams andLeptostroma anamorph ofHypoderma eucalyptii Cooke & Harkn, respectively. In both new strains the usual pattern of cyclosporins A to Z is not found. The structure elucidations of2 and3 are based on NMR spectroscopy, and biological data (immunosuppressive activity, cyclophilin-binding affinity and antifungal effects) are presented.

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References

  1. Borel JF, 1989. Pharmacology of cyclosporine (Sandimmune). Pharmacol Rev 41:259–371.

    Google Scholar 

  2. Dreyfuss M, E Härri, H Hofmann, H Kobel, W Pache and H Tscherter. 1976. Cyclosporin A and C, new metabolites fromTrichoderma polysporum. Eur J Appl Microbiol 3: 125–133.

    Google Scholar 

  3. Dreyfuss MM. 1986. Neue Erkenntnisse aus einem pharmakologischen Screening. Sydowia 39:22–36.

    Google Scholar 

  4. Dreyfuss MM, MH Schreier, H Tscherter and R Wenger (Sandoz Ltd). European Patent Application 0296 123A2 (June 15, 1988) [Chem Abstr 1989, 111: 152146a].

  5. Dreyfuss, MM. 1992. Ecology, microbial diversity and chemical creativity. In: New Drugs from Natural Sources (Coombes JD, ed), pp 59–62, IBC Technical Services Ltd. London, UK.

    Google Scholar 

  6. Dreyfuss MM and IH Chapela. 1994. Potential of fungi in the discovery of novel, low-molecular weight pharmaceuticals. In: The Discovery of Natural Products with Therapeutic Potential (Gullo VP, ed), pp 49–80, Butterworth-Heinemann Boston.

    Google Scholar 

  7. Farr DF, GF Bills, G Chamuris and AY Rossman. 1989. Fungi on Plants and Plant Products in the United States. APS Press, St Paul, Minnesota, USA, 1251 pp.

    Google Scholar 

  8. Gams W. 1971. Cephalosporium-artige Schimmelpilze (Hyphomycetes). Gustav Fischer Verlag, Stuttgart, 262 pp.

    Google Scholar 

  9. Gauze GF, LP Terekhova, TS Maximova, MG Brazhnikova, GF Federova and VN Borisova. 1983. Screening of new antibiotics of cyclosporin group. Antibiotiki 28:243–245.

    PubMed  Google Scholar 

  10. Goto T, T Kino, M Okuhara, H Tanaka, Y Tsurumi and S Takase (Fujisawa Co Ltd). Patent Application WO 92/13094 Japan (August 6, 1992).

  11. Handschumacher RE, MW Harding, J Rice, RJ Drugge and DW Speicher. 1984. Cyclophilin: a specific cytosolic binding protein for cyclosporin A. Science 226: 544–547.

    PubMed  Google Scholar 

  12. Hong L, X Tang, C Miao and Y Wang. 1984. Cyclosporin produced byFusarium solani sp no. 4-11. Isolation separation, purification and identification. Kangshengsu 9: 5–15.

    Google Scholar 

  13. Larson TG and DL Nuss. 1993. Cyclosporin-dependent stimulation of transcription by cyclosporin A. Proc Natl Acad Sci USA 90: 148–152.

    PubMed  Google Scholar 

  14. Lawen A and R Zocher. 1990. Cyclosporin synthetase, the most complex peptide synthesizing multienzyme so far described. J Biol Chem 265: 11355–11360.

    PubMed  Google Scholar 

  15. Lawen A, R Traber and D Geyl. 1991.In vitro biosynthesis of [Thr2,Leu5,D-Hiv8,Leu10]cyclosporin, a cyclosporin-related peptolide with immunosuppressive activity by a multienzyme polypeptide. J Biol Chem 266: 15567–15570.

    PubMed  Google Scholar 

  16. Lawen A and R Traber. 1993. Substrate specificities of cyclosporin synthetase and peptolide SDZ 214-103 synthetase. J Biol Chem 268: 20452–20465.

    PubMed  Google Scholar 

  17. Lawen A. 1996. Biosynthesis and mechanism of action of cyclosporins. In: Progress in Medicinal Chemistry (Ellis GP and DK Luscombe, eds), Vol 33, pp 53–97, Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  18. Loosli HR, H Kessler, H Oschkinat, HP Weber, TJ Petcher and A Widmer. 1985. The conformation of cyclosporin A in the crystal and in solution. Helv Chim Acta 68:682–704.

    Google Scholar 

  19. Moeller C, T Bühler and MM Dreyfuss. 1995. Intraspecific genetic diversity ofChaunopycnis alba detected by random amplified polymorphic DNA assay. Mycol Res 99: 681–688.

    Google Scholar 

  20. Moeller C, G Weber and MM Dreyfuss. 1996. Intraspecific diversity in the fungal speciesChaunopycnis alba; implications for microbial screening programs. J Ind Microbiol 17: 359–372.

    Google Scholar 

  21. Nakajima H, T Hamasaki, K Tanaka, Y Kimura, S Udagawa and Y Horie. 1989. Production of cyclosporin by fungi belonging to the genusNeocosmospord. Agric Biol Chem 53: 2291–2292.

    Google Scholar 

  22. Quesniaux VFJ, MH Schreier, RM Wenger, PC Hiestand, MW Harding and MHV Van Regenmortel. 1987. Cyclophilin binds to the region of cyclosporine involved in its immunosuppressive activity. Eur J Immunol 17: 1359–1365.

    PubMed  Google Scholar 

  23. Sakamoto K, E Tsujii M Miyauchi, T Nakanishi, M, Yamashita, N Shigematsu, T Tada, S Izumi and M Okuhara. 1993 FR901459, a novel immunosuppressant isolated fromStachybotrys chartarum No. 19392. J Antibiotics 46: 1788–1798.

    Google Scholar 

  24. Sawai K, T Okuno, Y Terada, Y Harada, K Sawamura, H Sasaki and S Takao. 1981. Isolation and properties of two antifungal substances fromFusarium solani. Agric Biol Chem 45: 1223–1228.

    Google Scholar 

  25. Schmidt B, D Riesner, A Lawen and H Kleinkauf. 1992. Cyclosporin synthetase is a 1.4 MDa multienzyme polypeptide. FEBS Lett 307: 355–360.

    PubMed  Google Scholar 

  26. Schreier MH, G Zenke, JF Borel and G Baumann. 1992. The continuing search for new immunomodulators. Transplant Proc 24 (Suppl 2): 19–21.

    PubMed  Google Scholar 

  27. Sutton BC. 1980. The Coelomycetes. Commonwealth Mycological Institute, Kew, Surrey, UK, 696 pp.

    Google Scholar 

  28. Traber R, H Hofmann, HR Loosli, M Ponelle and A von Wartburg. 1987. Neue Cyclosporine ausTolypocladium inflatum. Die Cyclosporine K-Z. Helv Chim Acta 70: 13–36.

    Google Scholar 

  29. Traber R, H Hofmann and H Kobel. 1989. Cyclosporins-new analogues by precursor directed biosynthesis. J Antibiotics 42: 591–597.

    Google Scholar 

  30. von Arx JA. 1981. The Genera of Fungi Sporulatung in Pure Culture. Cramer J, Vaduz, 424 pp.

    Google Scholar 

  31. von Arx JA, 1986.Tolypocladium, a synonym ofBeauveria. Mycotaxon 25: 153–158.

    Google Scholar 

  32. von Wartburg A and R Traber. 1986. Cyclosporins, fungal metabolites with immunosuppressive activities. In: Progress in Medicinal Chemistry (Ellis GP and GB West, eds), Vol 25, pp 1–33, Elsevier Science Publishers, Amsterdam.

    Google Scholar 

  33. Zocher R, U Keller, C Lee and K Hoffmann. 1992. A seventeen kilodaltons peptidyl-prolylcis-trans isomerase of the cyclosporin-producerTolypocladium inflatum is sensitive to cyclosporin A. J Antibiotics 45: 265–268.

    Google Scholar 

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  1. Preclinical Research, Sandoz Pharma Ltd, CH-4002, Basel, Switzerland

    R Traber & M M Dreyfuss

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  1. R Traber
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  2. M M Dreyfuss
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Traber, R., Dreyfuss, M.M. Occurrence of cyclosporins and cyclosporin-like peptolides in fungi. Journal of Industrial Microbiology & Biotechnology 17, 397–401 (1996). https://doi.org/10.1007/BF01574770

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  • DOI: https://doi.org/10.1007/BF01574770

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