Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Special Feature: Article
  • Published:

Epipolythiodiketopiperazine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma cf. brevicompactum

The Journal of Antibiotics volume 73, pages 559–567 (2020)Cite this article

Subjects

Abstract

The marine-derived fungus Trichoderma sp. TPU199 (cf. Trichoderma brevicompactum) produces pretrichodermamide A (1) and gliovirin (2), which possess a rare type of epipolythiodiketopiperazine (ETP) structure with a disulfide bridge between the α- and β-positions of two amino acid residues. We previously reported that this strain gave the halogenated ETPs, DC1149B (4), DC1149R (6), and iododithiobrevamide (7), when fermented with sodium halides (NaCl, NaBr, and NaI). Further analyses of the metabolites obtained under NaI-containing culture conditions resulted in the isolation of two new ETP derivatives (11 and 12) and three new trichothecene sesquiterpenes (13–15). The structures of 11 and 12, including their absolute configurations, were elucidated based on spectroscopic data for 11 and 12 and comparisons with those for 1 and related compounds, revealing that 11 was an epimer of 1 at the C-5 position and 12 was a trithio-derivative of 11. The structures of 13–15 were established by analyzing their 1D and 2D NMR data. The absolute configurations of 13–15 were assigned by comparing their experimental electronic circular dichroism (ECD) spectra with the calculated ECD spectrum of 13.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Genilloud O. Actinomycetes: still a source of novel antibiotics. Nat Prod Rep. 2017;34:1203–32.

    Article  CAS  PubMed  Google Scholar 

  2. Schueffler A, Anke T. Fungal natural products in research and development. Nat Prod Rep. 2014;31:1425–48.

    Article  CAS  PubMed  Google Scholar 

  3. Omura S. Microbial metabolites: 45 years of wandering, wondering and discovering. Tetrahedron. 2011;67:6420–59.

    Article  CAS  Google Scholar 

  4. Butler MS, Blaskovich MA, Cooper MA. Antibiotics in the clinical pipeline at the end of 2015. J Antibiot. 2017;70:3–24.

    Article  CAS  PubMed  Google Scholar 

  5. Butle MS, Robertson AA, Cooper MA. Natural product and natural product derived drugs in clinical trials. Nat Prod Rep. 2014;31:1612–61.

    Article  Google Scholar 

  6. Sanchez JF, Somoza AD, Keller NP, Wang CC. Advances in Aspergillus secondary metabolite research in the post-genomic era. Nat Prod Rep. 2012;29:351–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scherlach K, Hertweck CH. Triggering cryptic natural product biosynthesis in microorganisms. Org Biomol Chem. 2009;7:1753–60.

    Article  CAS  PubMed  Google Scholar 

  8. Zarins-Tutt JS, et al. Prospecting for new bacterial metabolites: a glossary of approaches for inducing, activating and upregulating the biosynthesis of bacterial cryptic or silent natural products. Nat Prod Rep. 2016;33:54–72.

    Article  CAS  PubMed  Google Scholar 

  9. Seephonkai P, Kongsaeree P, Prabpai S, Isaka M, Thebtaranonth Y. Transformation of an irregularly bridged epidithiodiketopiperazine to trichodermamide A. Org Lett. 2006;8:3073–5.

    Article  CAS  PubMed  Google Scholar 

  10. Stipanovic RD, Howell CR. The structure of gliovirin, a new antibiotic from Gliocladium virens. J Antibiot. 1982;35:1326–30.

    Article  CAS  PubMed  Google Scholar 

  11. Stipanovic RD, Howell CR, Hedin PA. Biosynthesis of gliovirin: incorporation of L-phenylalanine (1-13C). J Antibiot. 1994;47:942–4.

    Article  CAS  PubMed  Google Scholar 

  12. Garo E, et al. Trichodermamides A and B, cytotoxic modified dipeptides from the marine-derived fungus Trichoderma virens. J Nat Prod. 2003;66:423–6.

    Article  CAS  PubMed  Google Scholar 

  13. Yamazaki H, Rotinsulu H, Narita R, Takahashi R, Namikoshi M. Induced production of halogenated epidithiodiketopiperazines by a marine-derived Trichoderma cf. brevicompactum with sodium halides. J Nat Prod. 2015;78:2319–21.

    Article  CAS  PubMed  Google Scholar 

  14. Welch TR, Williams RM. Epidithiodioxopiperazines. occurrence, synthesis and biogenesis. Nat Prod Rep. 2014;31:1376–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nakano H, et al. DC1149B, DC1149R and production thereof. Japan: Patent Kokai; 1990: 218686. Accessed 31 Aug 1990.

  16. Yamazaki H, Takahashi O, Murakami K, Namikoshi M. Induced production of a new unprecedented epitrithiodiketopiperazine, chlorotrithiobrevamide, by a culture of the marine-derived Trichoderma cf. brevicompactum with dimethyl sulfoxide. Tetrahedron Lett. 2015;56:6262–5.

    Article  CAS  Google Scholar 

  17. Kajula M, et al. Bridged epipolythiodiketopiperazines from Penicillium raciborskii, an endophytic fungus of Rhododendron tomentosum Harmaja. J Nat Prod. 2016;79:685–90.

    Article  CAS  PubMed  Google Scholar 

  18. Zhu M, et al. Penicisulfuranols A–F, alkaloids from the mangrove endophytic fungus Penicillium janthinellum HDN13-309. J Nat Prod. 2017;80:71–5.

    Article  CAS  PubMed  Google Scholar 

  19. Yamazaki H, Rotinsulu H, Takahashi O, Kirikoshi R, Namikoshi M. Induced production of a new dipeptide with a disulfide bridge by long-term fermentation of marine-derived Trichoderma cf. brevicompactum. Tetrahedron Lett. 2016;57:5764–7.

    Article  CAS  Google Scholar 

  20. Yurchenko AN, et al. Pretrichodermamides D–F from a marine algicolous fungus Penicillium sp. KMM 4672. Mar Drugs. 2016;14:E122.

    Article  CAS  PubMed  Google Scholar 

  21. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of yeasts. CLSI document M27-A3. 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

  22. Clinical and Laboratory Standards Institute (CLSI). Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard CLSI document M38-A2. 3rd ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2008.

Download references

Acknowledgements

This work was supported in part by JSPS KAKENHI Grant Numbers 25870660 and 16K21310 to HY, the Takeda Science Foundation to HY, and the Foundation for Japanese Chemical Research to HY. Calculations by Gaussian 09 were performed using supercomputing resources at the Cyberscience Center, Tohoku University. We are grateful to Mr T. Matsuki and S. Sato of Tohoku Medical and Pharmaceutical University for measuring mass spectra.

Author information

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Aoba-ku, Sendai, 981-8558, Japan

    Hiroyuki Yamazaki, Ohgi Takahashi, Ryota Kirikoshi, Akiho Yagi, Teruki Ogasawara, Yuki Bunya, Henki Rotinsulu, Ryuji Uchida & Michio Namikoshi

  2. Faculty of Mathematic and Natural Sciences, Sam Ratulangi University, Kampus Bahu, Manado, 95115, Indonesia

    Henki Rotinsulu

Authors
  1. Hiroyuki Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ohgi Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryota Kirikoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akiho Yagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teruki Ogasawara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuki Bunya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Henki Rotinsulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryuji Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michio Namikoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroyuki Yamazaki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Dedicated to Professor William Fenical in recognition of his contributions to the development of marine natural product chemistry.

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamazaki, H., Takahashi, O., Kirikoshi, R. et al. Epipolythiodiketopiperazine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma cf. brevicompactum. J Antibiot 73, 559–567 (2020). https://doi.org/10.1038/s41429-020-0314-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-020-0314-5

This article is cited by

Search

Advanced search

Quick links