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.

Isolation of new derivatives of the 20-membered macrodiolide bispolide from Kitasatospora sp. MG372-hF19

The Journal of Antibiotics volume 75, pages 77–85 (2022)Cite this article

Subjects

Abstract

New three macrocyclic diolides, named bispolides C-E (1–3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we reported previously. The absolute structures of compounds 1–3 were elucidated by NMR and X-ray crystallography. Compounds 1–3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1–3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1–3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. Gazdar AF, Bunn PA, Minna JD. Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer. 2017;17:725–37.

    Article  CAS  Google Scholar 

  2. Bunn PA Jr, Minna JD, Augustyn A, Gazdar AF, Ouadah Y, Krasnow MA, et al. Small cell lung cancer: can recent advances in biology and molecular biology be translated into improved outcomes? J Thorac Oncol 2016;11:453–74.

    Article  Google Scholar 

  3. Arcamone FM, Bertazzoli C, Ghione M, Scotti TG. Melanosporin and elaiophylin, new antibiotics from Streptomyces melanosporus (sive melonsporofaciens) n. sp. Gion. Microbial. 1959;7:207–16.

    CAS  Google Scholar 

  4. Arai M. Azalomycins B and F, two new antibiotics. I. Production and isolation. J Antibiot. 1960;13:46–50.

    CAS  Google Scholar 

  5. Zhao X, Fang Y, Yang Y, Qin Y, Wu P, Wang T, et al. Elaiophylin, a novel autophagy inhibitor, exerts anti-tumor activity as a single agent in ovarian cancer cells. Autophagy. 2015;11:1849–63.

    Article  CAS  Google Scholar 

  6. Okujo N, Iinuma H, George A, Eim KS, Li TL, Ting NS, et al. Bispolides, Novel 20-Membered Ring Macrodiolide Antibiotics from Microbispora. J Antibiot. 2007;60:216–9.

    Article  CAS  Google Scholar 

  7. Otoguro K, Iwatsuki M, Ishiyama A, Namatame M, Nishihara-Tsukashima A, Sato S, et al. In vitro and in vivo antiprotozoal activities of bispolides and their derivatives. J Antibiot. 2010;63:275–7.

    Article  CAS  Google Scholar 

  8. Kohda Y, Sakamoto S, Otsuka Y, Sawa R, Kubota Y, Igarashi M, et al. A new indole glycoside from Kitasatospora sp. MG372-hF19 carrying a 6-deoxy-α-L-talopyranose moiety. J Antibiot. 2020;73:167–70.

    Article  CAS  Google Scholar 

  9. Clinical and Laboratory Standards Institute (CLSI). Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved Standard, 8th ed. M7-A8; Wayne, PA, USA: CLSI; 2009.

  10. Dan S, Tsunoda T, Kitahara O, Yanagawa R, Zembutsu H, Katagiri T, et al. An integrated database of chemosensitivity to 55 anticancer drugs and gene expression profiles of 39 human cancer cell lines. Cancer Res. 2002;62:1139–47.

    CAS  PubMed  Google Scholar 

  11. Kong D, Yamori T. JFCR39, a panel of 39 human cancer cell lines, and its application in the discovery and development of anticancer drugs. Bioorg Med Chem. 2012;20:1947–51.

    Article  CAS  Google Scholar 

  12. Wu C, Tan Y, Gan M, Wang Y, Guan Y, Hu X, et al. Identification of elaiophylin derivatives from the marine-derived actinomycete Streptomyces sp. 7-145 using PCR-based screening. J Nat Prod. 2013;76:2153–7.

    Article  CAS  Google Scholar 

  13. Gui M, Zhang M, Wu W, Sun P. Natural occurrence, bioactivity and biosynthesis of elaiophylin analogues. Molecules. 2019;24:3840.

    Article  CAS  Google Scholar 

  14. Williams JD, Sefton AM. Comparison of macrolide antibiotics. J Antimicrob Chemother. 1993;31 Suppl. C:11–26.

    Article  CAS  Google Scholar 

  15. Wang G, Zhou P, Chen X, Zhao L, Tan J, Yang Y, et al. The novel autophagy inhibitor elaiophylin exerts anti-tumor activity against multiple myeloma with mutant TP53 in part through endoplasmic reticulum stress-induced apoptosis. Cancer Biol Ther. 2017;18:584–95.

    Article  CAS  Google Scholar 

  16. Grigoriev PA, Schlegel R, Grafe U. Cation selective ion channels formed by macrodiolide antibiotic elaiophylin in lipid bilayer membranes. Bioelectrochemistry. 2001;54:11–5.

    Article  CAS  Google Scholar 

  17. Papini E, Sandona D, Rappuoli R, Montecucco C. On the membrane translocation of diphtheria toxin: at low pH the toxin induces ion channels on cells. EMBO J. 1988;7:3353–9.

    Article  CAS  Google Scholar 

  18. Katayama H, Kusaka Y, Yokota H, Akao T, Kojima M, Nakamura O, et al. Parasporin-1, a novel cytotoxic protein from Bacillus thuringiensis, induces Ca2+ influx and a sustained elevation of the cytoplasmic Ca2+ concentration in toxin-sensitive cells. J Biol Chem. 2007;282:7742–52.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. I. Momose and Mr. S. Ohba for technical assistance and discussion. The authors also thank the Molecular Profiling Committee, Grant-in-Aid for Scientific Research on Innovative Areas “Advanced Animal Model Support (AdAMS)” from The Ministry of Education, Culture, Sports, Science and Technology, Japan (JSPS KAKENHI Grant Number JP 16H06276). This work was supported in part by grants from JSPS KAKENHI Grant Number 17K08777.

Author information

Authors and Affiliations

  1. Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Shizuoka, Japan

    Yasuko Kohda, Shuichi Sakamoto & Manabu Kawada

  2. Institute of Microbial Chemistry (BIKAKEN), Laboratory of Microbiology, Microbial Chemistry Research Foundation, Tokyo, Japan

    Maya Umekita, Rie Arisaka, Yuko Shibuya, Hideyuki Muramatsu & Masayuki Igarashi

  3. Institute of Microbial Chemistry (BIKAKEN), Laboratory of Molecular Structure Analysis, Microbial Chemistry Research Foundation, Tokyo, Japan

    Tomoyuki Kimura, Yumiko Kubota & Ryuichi Sawa

  4. Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    Shingo Dan

  5. Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, Tokyo, Japan

    Manabu Kawada

Authors
  1. Yasuko Kohda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuichi Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maya Umekita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomoyuki Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yumiko Kubota
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rie Arisaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuko Shibuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hideyuki Muramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryuichi Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shingo Dan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Manabu Kawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Masayuki Igarashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shuichi Sakamoto or Masayuki Igarashi.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kohda, Y., Sakamoto, S., Umekita, M. et al. Isolation of new derivatives of the 20-membered macrodiolide bispolide from Kitasatospora sp. MG372-hF19. J Antibiot 75, 77–85 (2022). https://doi.org/10.1038/s41429-021-00492-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-021-00492-5

Search

Advanced search

Quick links