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.

  • Article
  • Published:

Discovery of diketopiperazine alkaloids from an endophytic Kitasatospora sp. by heterologous expression

The Journal of Antibiotics volume 79, pages 309–315 (2026)Cite this article

Subjects

Abstract

Heterologous expression of a tRNA-dependent cyclodipeptide synthase (CDPS)-containing biosynthetic gene cluster from the endophytic Kitasatospora sp. CPCC204717 resulted in the discovery of two novel diastereoisomeric 3-hydroxy-2-oxindole diketopiperazine alkaloids (1–2) along with three known congeners cyclo-l-tryptophan-l-tryptophan (3), guanitrypmycin C3-2 (4), and guanitrypmycin C3-1 (5). Their structures were elucidated by extensive spectroscopic analyses combined with ECD calculations. Compound 2 exhibited antibacterial activities against Staphylococcus aureusa while 1–5 displayed binding affinities and inhibitory effects against CYP121.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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. Takahashi Y. Genus Kitasatospora, taxonomic features and diversity of secondary metabolites. J Antibiot. 2017;70:506–13.

    Article  CAS  Google Scholar 

  2. Wei Y, Wang G, Li Y, Gan M. The secondary metabolites from genus Kitasatospora: a promising source for drug discovery. Chem Biodivers. 2024;21:e202401473.

    Article  CAS  PubMed  Google Scholar 

  3. Momose I, Watanabe T. Tyropeptins, proteasome inhibitors produced by Kitasatospora sp. MK993-dF2. J Antibiot. 2017;70:542–50.

    Article  CAS  Google Scholar 

  4. Illigmann A, et al. Structure of Staphylococcus aureus ClpP bound to the covalent active-site inhibitor Cystargolide A. Angew Chem Int Ed Engl. 2024;63:e202314028.

    Article  CAS  PubMed  Google Scholar 

  5. Zhou Y, et al. Phenazines contribute to microbiome dynamics by targeting topoisomerase IV. Nat Microbiol. 2025;10:2396–411.

    Article  CAS  PubMed  Google Scholar 

  6. Jia J, et al. 2,5-Diketopiperazines: A review of source, synthesis, bioactivity, structure, and MS fragmentation. Curr Med Chem. 2023;30:1060–85.

    Article  CAS  PubMed  Google Scholar 

  7. Skinnider MA, Johnston CW, Merwin NJ, Dejong CA, Magarvey NA. Global analysis of prokaryotic tRNA-derived cyclodipeptide biosynthesis. BMC Genomics. 2018;19:45.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lautru S, Gondry M, Genet R, Pernodet JL. The albonoursin gene cluster of S noursei biosynthesis of diketopiperazine metabolites independent of nonribosomal peptide synthetases. Chem Biol. 2002;9:1355–64.

    Article  CAS  PubMed  Google Scholar 

  9. Meng S, et al. A six-oxidase cascade for tandem C-H bond activation revealed by reconstitution of Bicyclomycin biosynthesis. Angew Chem Int Ed Engl. 2018;57:719–23.

    Article  CAS  PubMed  Google Scholar 

  10. Belin P, et al. Identification and structural basis of the reaction catalyzed by CYP121, an essential cytochrome P450 in Mycobacterium tuberculosis. Proc Natl Acad Sci. 2009;106:7426–31.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Cochrane JR, White JM, Wille U, Hutton CA. Total synthesis of mycocyclosin. Org Lett. 2012;14:2402–5.

    Article  CAS  PubMed  Google Scholar 

  12. Hao X, et al. Zelkovamycins B–E, cyclic octapeptides containing rare amino acid residues from an Endophytic Kitasatospora sp. Org Lett. 2020;22:9346–50.

    Article  CAS  PubMed  Google Scholar 

  13. Hao X, et al. Zelkovamycins F and G, Cyclopeptides with Cα-methyl-threonine residues, from an Endophytic Kitasatospora sp. J Nat Prod. 2022;85:1715–22.

    Article  CAS  PubMed  Google Scholar 

  14. Shiono Y, Akiyama K, Hayashi H. New Okaramine congeners, Okamines J, K, L, M and related compounds, from Penicillium simplicissimum ATCC 90288. Biosci Biotechnol Biochem. 1999;63:10–1920.

    Article  Google Scholar 

  15. Yu H, Xie X, Li S. Coupling of Guanine with cyclo-l-Trp-l-Trp mediated by a Cytochrome P450 homologue from Streptomyces purpureus. Org Lett. 2018;20:4921–4925.

    Article  CAS  PubMed  Google Scholar 

  16. Yu H, Xie X, Li S. Coupling of cyclo-l-Trp-l-Trp with Hypoxanthine increases the structure diversity of Guanitrypmycins. Org Lett. 2019;21:9104–8.

    Article  CAS  PubMed  Google Scholar 

  17. Maes CM, Potgieter M, Steyn PS. N.m.r. assignments, conformation, and absolute configuration of ditryptophenaline and model dioxopiperazines. J Chem Soc Perkin Trans. 1986;1:861–6.

    Article  Google Scholar 

  18. Fujii K, Ikai Y, Oka H, Suzuki M, Harada K-i. A nonempirical method using LC/MS for determination of the absolute configuration of constituent amino acids in a peptide:  combination of Marfey’s method with mass spectrometry and its practical application. Anal Chem. 1997;69:5146–51.

    Article  CAS  Google Scholar 

  19. Kishk SM, et al. Synthesis and biological evaluation of novel cYY analogues targeting Mycobacterium tuberculosis CYP121A1. Bioorg Med Chem. 2019;27:1546–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walter I, et al. Structure-activity relationship and mode-of-action studies highlight 1-(4-Biphenylylmethyl)-1H-imidazole-derived small molecules as potent CYP121 inhibitors. ChemMedChem. 2021;16:2786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wei C, et al. 3-Hydroxy-2-oxindole Derivatives containing sulfonamide motif: synthesis, antiviral activity, and modes of action. J Agric Food Chem. 2023;71:267–75.

    Article  CAS  PubMed  Google Scholar 

  22. Bruhn T, Schaumlöffel A, Hemberger Y, Bringmann G. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013;25:243–9.

    Article  CAS  PubMed  Google Scholar 

  23. Li J, Wei Y, Wang G, Li Y, Gan M. A new Azaphilone derivative from the co-culture of Aspergillus versicolor and Aspergillus chevalieri. Rec Nat Prod. 2025;2025:198–203.

    Google Scholar 

Download references

Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (Grant nos. 82204254, 82273830) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-055). We thank Prof. Yishuang Liu and Xiao Wang (IMB, CAMS) for their help during biological evaluation, Prof. Liyan Yu, China Pharmaceutical Culture Collection (NMRC-2024-3) for the kind gift of the strain CPCC204717, and the HPCC of Peking Union Medical College for computational facilities.

Author information

Author notes

  1. These authors contributed equally: Guiyang Wang, Yuanjuan Wei

Authors and Affiliations

  1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Guiyang Wang, Yuanjuan Wei, Yan Li & Maoluo Gan

Authors
  1. Guiyang Wang
    View author publications

    Search author on:PubMed Google Scholar

  2. Yuanjuan Wei
    View author publications

    Search author on:PubMed Google Scholar

  3. Yan Li
    View author publications

    Search author on:PubMed Google Scholar

  4. Maoluo Gan
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Yan Li or Maoluo Gan.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, G., Wei, Y., Li, Y. et al. Discovery of diketopiperazine alkaloids from an endophytic Kitasatospora sp. by heterologous expression. J Antibiot 79, 309–315 (2026). https://doi.org/10.1038/s41429-026-00908-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41429-026-00908-0

Search

Advanced search

Quick links