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A new pyranonaphthoquinone, actinoquinonal A, and its congeners from the combined-culture of Streptomyces sp. 23–50 and Tsukamurella pulmonis TP-B0596

The Journal of Antibiotics volume 78, pages 350–358 (2025)Cite this article

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Abstract

The combined-culture of actinomycetes with mycolic acid-containing bacteria (MACB) Tsukamurella pulmonis TP-B0596 is a promising strategy to produce cryptic metabolites in actinomycetes. In this study, Streptomyces sp. 23-50 was identified as an appropriate strain for co-culturing with T. pulmonis TP-B0596 using on-gel combined-culture screening of 160 strains of actinomycetes. A new pyranonaphthoquinone, actinoquinonal A (1), along with two known congeners, compound 2 and mevashuntin (3), were isolated from the combined-culture of Streptomyces sp. 23-50 with T. pulmonis TP-B0596 based on global natural product social (GNPS) molecular networking. The planar structures of 1–3 were elucidated by analyzing 2D nuclear magnetic resonance (NMR) and LC-MS/MS spectral data, and the absolute configurations of 1 and 3 were unambiguously determined by comparing experimental and calculated ECD spectra. Moreover, the combined-culture characteristic metabolites, including 3, were enhanced when Streptomyces sp. 23-50 was cultured in the presence of pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the mevalonate pathway, suggesting that T. pulmonis TP-B0596 triggered a shunt in the mevalonate pathway of Streptomyces sp. 23-50. Notably, compounds 1 and 3 exhibited cytotoxicity against human cervical epithelioid carcinoma HeLa S3 (IC50 = 60.5 μM for 1, 0.67 μM for 3) and human colorectal cancer HT29 cells (IC50 = 101.9 μM for 1, 0.45 μM for 3).

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Data availability

The Supporting Information is available at https://doi.org/10.1038/s41429-025-00821-y. Experimental detail; 1D and 2D NMR spectra, HRMS spectra, and IR spectrum for 1, 1H NMR spectra for 2 and 3, CD spectrum for 3.

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Acknowledgements

This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H06401, 19H02840, 22H04901, 23H04882, and 24H00493; all awarded to H. Kakeya), the Project for Promotion of Cancer Research and Therapeutic Evolution (JP24ama221540 and JP25ama221540 to H. Kakeya), and the Platform Project for Supporting Drug Discovery and Life Science Research (JP24ama121034 and JP25ama121034 to H. Kakeya) from the Japan Agency for Medical Research and Development (AMED), Japan. HOKUSAI (RIKEN) provided the computer resources for the DFT calculations. We acknowledge Ms. Mikiko Ito (RIKEN) for assistance with the computational work.

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Author notes

  1. Kensuke Kaneko

    Present address: Advanced Instruments Center, Kyushu Sangyo University, Fukuoka, Japan

  2. Shinichi Nishimura

    Present address: Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan

  3. These authors contributed equally: Kazuki Yanagisawa, Kensuke Kaneko.

Authors and Affiliations

  1. Department of System Chemotherapy and Molecular Sciences, Division of Medicinal Frontier Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan

    Kazuki Yanagisawa, Kensuke Kaneko, Hiroaki Ikeda, Sumika Iwata, Noeka Nagao, Susumu Watari, Shinichi Nishimura & Hideaki Kakeya

  2. RIKEN Center for Sustainable Resource Science, Saitama, Japan

    Atsuya Muranaka & Hiroyuki Koshino

  3. Tropical Biosphere Research Center, University of the Ryukyus, Okinawa, Japan

    Naoya Shinzato

  4. Faculty of Science, Gakushuin University, Tokyo, Japan

    Hiroyasu Onaka

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Correspondence to Hideaki Kakeya.

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Yanagisawa, K., Kaneko, K., Ikeda, H. et al. A new pyranonaphthoquinone, actinoquinonal A, and its congeners from the combined-culture of Streptomyces sp. 23–50 and Tsukamurella pulmonis TP-B0596. J Antibiot 78, 350–358 (2025). https://doi.org/10.1038/s41429-025-00821-y

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