Brief Communication | Published:

Divergent biosynthesis yields a cytotoxic aminomalonate-containing precolibactin

Nature Chemical Biology volume 12, pages 773775 (2016) | Download Citation

Abstract

Colibactin is an as-yet-uncharacterized genotoxic secondary metabolite produced by human gut bacteria. Here we report the biosynthetic discovery of two new precolibactin molecules from Escherichia coli, including precolibactin-886, which uniquely incorporates the highly sought genotoxicity-associated aminomalonate building block into its unprecedented macrocyclic structure. This work provides new insights into the biosynthetic logic and mode of action of this colorectal-cancer-linked microbial chemical.

  • Compound

    tetradecanoyl-D-asparaginyl-L-alanine

  • Compound

    (S)-4-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)pentanoic acid

  • Compound

    (R)-N1-((S)-5-oxohexan-2-yl)-2-tetradecanamidosuccinamide

  • Compound

    (R)-N1-((S)-7-((1-acetylcyclopropyl)amino)-5,7-dioxoheptan-2-yl)-2-tetradecanamidosuccinamide

  • Compound

    (R)-N1-((S)-5-(7-methyl-5-oxo-4-azaspiro[2.4]hept-6-en-6-yl)-5-oxopentan-2-yl)-2-tetradecanamidosuccinamide

  • Compound

    2-(4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)acetic acid

  • Compound

    2-((4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)methyl)thiazole-4-carboxylic acid

  • Compound

    (2-((4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)methyl)thiazole-4-carbonyl)-L-cysteine

  • Compound

    2'-((4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)methyl)-[2,4'-bithiazole]-4-carboxylic acid

  • Compound

    2-((Z)-2'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-5'-hydroxy-5',7',10'-trioxospiro[cyclopropane-1,8'-4,9-diaza-1(5,2)-oxazola-2(4,2)-thiazolacycloundecaphan]-4'-yl)thiazole-4-carboxylic acid

  • Compound

    S-(2-acetamidoethyl) (S)-2-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)propanethioate

  • Compound

    S-(2-acetamidoethyl) (R)-2-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)propanethioate

  • Compound

    S-(2-acetamidoethyl) (S)-4-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)pentanethioate

  • Compound

    S-(2-acetamidoethyl) 2-(4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)ethanethioate

  • Compound

    S-(2-acetamidoethyl) 2-((4'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-3',6'-dioxo-2',3'-dihydrospiro[cyclopropane-1,1'-pyrrolo[3,4-c]pyridin]-5'(6'H)-yl)methyl)thiazole-4-carbothioate

  • Compound

    S-(2-acetamidoethyl) 2-((Z)-2'-((S)-3-((R)-4-amino-4-oxo-2-tetradecanamidobutanamido)butyl)-5'-hydroxy-5',7',10'-trioxospiro[cyclopropane-1,8'-4,9-diaza-1(5,2)-oxazola-2(4,2)-thiazolacycloundecaphan]-4'-yl)thiazole-4-carbothioate

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Acknowledgements

This work was generously supported by grants from the China Ocean Mineral Resources Research and Development Association (13.5 program to P.-Y.Q.) and the NIH (R01-GM85770 to B.S.M.). We thank P.R. Jensen, J. Busch, C.B. Naman, and Y.K. Tam for technical advice and access to equipment.

Author information

Author notes

    • Zhong-Rui Li
    •  & Jie Li

    These authors contributed equally to this work.

Affiliations

  1. Division of Life Science and Environmental Science Programs, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

    • Zhong-Rui Li
    • , Jennifer Y H Lai
    • , Wei-Peng Zhang
    • , Yong-Xin Li
    •  & Pei-Yuan Qian
  2. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, California, USA.

    • Jie Li
    •  & Bradley S Moore
  3. High-field NMR Research Center, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.

    • Jin-Ping Gu
    •  & Dong-Hai Lin
  4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.

    • Brendan M Duggan
    •  & Bradley S Moore
  5. Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.

    • Zhi-Long Li
    •  & Rong-Biao Tong
  6. Shenzhen Key Laboratory of Marine Bioresource & Ecoenvironmental Science, Shenzhen Engineering Laboratory for Marine Algal Biotechnology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.

    • Ying Xu

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Contributions

Z.-R.L., J.L., J.-P.G., J.Y.H.L., B.M.D., W.-P.Z., Z.-L.L., Y.-X.L., R.-B.T., Y.X., and D.-H.L. performed experiments and collected data; all authors analyzed data; Z.-R.L., J.L., B.S.M., and P.-Y.Q. designed the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bradley S Moore or Pei-Yuan Qian.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Results, Supplementary Tables 1–3 and Supplementary Figures 1–18.

  2. 2.

    Supplementary Note

    Supplementary Notes 1–3.

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DOI

https://doi.org/10.1038/nchembio.2157

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