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Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds

Nature Chemical Biology volume 7, pages 304–309 (2011)Cite this article

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An Addendum to this article was published on 17 April 2015

Abstract

In the search for new efficacious antibiotics, biosynthetic engineering offers attractive opportunities to introduce minor alterations to antibiotic structures that may overcome resistance. Dbv29, a flavin-containing oxidase, catalyzes the four-electron oxidation of a vancomycin-like glycopeptide to yield A40926. Structural and biochemical examination of Dbv29 now provides insights into residues that govern flavinylation and activity, protein conformation and reaction mechanism. In particular, the serendipitous discovery of a reaction intermediate in the crystal structure led us to identify an unexpected opportunity to intercept the normal enzyme mechanism at two different points to create new teicoplanin analogs. Using this method, we synthesized families of antibiotic analogs with amidated and aminated lipid chains, some of which showed marked potency and efficacy against multidrug resistant pathogens. This method offers a new strategy for the development of chemical diversity to combat antibacterial resistance.

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Figure 1
Figure 2: The structure of Dbv29 and its enzymatic mechanism.
Figure 3: Intermediate trapping strategies to probe the catalytic mechanism.
Figure 4: Variations in acyl chain length regulate the resultant glycopeptide analog.

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Acknowledgements

The research was supported by the National Science Council of Taiwan (grants 96-2628-B-001-026-MY3 and 98-2311-B-001-014-MY3 to T.-L.L.) and Academia Sinica intramural funding. X-ray diffraction was carried out at the Protein Crystallography Facility at the National Synchrotron Radiation Research Center, supported by the National Research Program for Genomic Medicine and the National Science Council of Taiwan. We thank C.-Y. Wu (Academia Sinica) for providing 5-azide pentylamine.

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Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Yu-Chen Liu, Yi-Shan Li, Syue-Yi Lyu, Li-Jen Hsu, Yu-Hou Chen, Yu-Ting Huang, Hsiu-Chien Chan, Chuen-Jiuan Huang, Gan-Hong Chen, Ming-Daw Tsai & Tsung-Lin Li

  2. Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan

    Yu-Chen Liu

  3. Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan

    Yu-Chen Liu & Ming-Daw Tsai

  4. Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan

    Syue-Yi Lyu

  5. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

    Yu-Hou Chen & Ming-Daw Tsai

  6. National Synchrotron Radiation Research Center, Hsinchu, Taiwan

    Chia-Cheng Chou

  7. Biotechnology Center, National Chung Hsing University, Taichung, Taiwan

    Tsung-Lin Li

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Contributions

T.-L.L. designed research; Y.-C.L. solved the structures; H.-C.C. and C.-C.C. helped refinement; Y.-S.L., S.-Y.L., C.-J.H., Y.-T.H. and G.-H.C. performed biochemical experiments; Y.-H.C. and Y.-C.L. performed analytical ultracentrifuge analysis; L.-J.H. performed animal tests. T.-L.L. and M.-D.T. provided supervision; T.-L.L. and M.-D.T. wrote the paper.

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Correspondence to Tsung-Lin Li.

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Supplementary Methods, Supplementary Figures 1–19 and Supplementary Tables 1–4 (PDF 6641 kb)

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Liu, YC., Li, YS., Lyu, SY. et al. Interception of teicoplanin oxidation intermediates yields new antimicrobial scaffolds. Nat Chem Biol 7, 304–309 (2011). https://doi.org/10.1038/nchembio.556

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