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Structure-based molecular networking for the target discovery of novel germicidin derivatives from the sponge-associated streptomyces sp. 18A01

The Journal of Antibiotics volume 74, pages 799–806 (2021)Cite this article

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Abstract

Four new α-pyrone derivatives, named germicidins P-S (1-4) along with nine known analogues (5-13) were discovered from the sponge-associated Streptomyces sp. 18A01 guided by Global Natural Products Social (GNPS) molecular networking, the LC-DAD-MS profile, and hexokinase II (HK2) inhibitory activity. The structures of 1-13 were elucidated by analysis of their HRMS, optical rotation, and NMR spectroscopic data. The absolute configurations of germicidin P (1) and germicidin Q (2) were determined on the basis of comparisons of experimental and theoretically calculated ECD spectra. Bioactivities of the isolated compounds were assayed against human HK2. The bioassay results showed that compounds 1-4 and 11-13 exhibited significant inhibitory activities against HK2, with IC50 values ranging from 5.1 to 11.0 μM. A molecular docking simulation demonstrated that these germicidins were docked in the inner active site tunnel of HK2. Interestingly, the amino residue Arg91 has a better binding affinity and efficacy than the amino residue Asn89 in the process of HK2 binding to the ligands, resulting in better hexokinase inhibitory activity. This result provided a valuable perspective for better understanding their HK2 inhibition activity.

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Acknowledgements

This work was funded by the Doctoral Start-up Foundation of Liaoning Province (2019-BS-258), the National Natural Science Foundation of China (31872036, 41776178, and 41576136), the Liaoning Revitalization Talents Program (XLYC1807268), the Open Subject of Guangdong key Laboratory of Marine Materia Medica (LMM2020-9), and the Youth Innovation Promotion Association CAS (2018229).

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Authors and Affiliations

  1. Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, People’s Republic of China

    Yan Bai, Jiangchun Hu, Ying Wang & Huaqi Pan

  2. The Key Laboratory of Chemistry for Natural Product of Guizhou Province and Chinese Academy of Sciences, Guiyang, People’s Republic of China

    Ping Yi

  3. South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, People’s Republic of China

    Yun Zhang & Jianhua Ju

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  1. Yan Bai
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Contributions

YB conducted the experiments. PY performed the ECD calculations. YW performed the LC-MS/MS analysis. YZ and JJ collected the sponge and revised the manuscript. JH revised the manuscript. HP isolated strain 18A01 and designed the experiments. YB and HP analyzed the data and wrote the manuscript. All authors approved the manuscript.

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Correspondence to Huaqi Pan.

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Bai, Y., Yi, P., Zhang, Y. et al. Structure-based molecular networking for the target discovery of novel germicidin derivatives from the sponge-associated streptomyces sp. 18A01. J Antibiot 74, 799–806 (2021). https://doi.org/10.1038/s41429-021-00447-w

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