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Precursor-directed biosynthesis and biological activity of tripropeptin Cpip, a new tripropeptin C analog containing pipecolic acid

The Journal of Antibiotics volume 77, pages 238–244 (2024)Cite this article

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Abstract

Tripropeptin C, a non-ribosomal cyclic lipopeptide containing three proline residues, exhibits excellent efficacy in the mouse-methicillin-resistant Staphylococcus aureus septicemia model. Since tripropeptins contain L-prolyl-D-proline and, as a result, are known to form a hairpin structure in proteins, it was of interest to determine whether this substructure contributes to their antibacterial activity. In this study, prolines in tripropeptin C were replaced with pipecolic acid(s) using precursor-directed biosynthesis. Only a new tripropeptin analog, tripropeptin Cpip, which has one L-pipecolic acid in place of L-proline, was isolated. The in vitro antimicrobial activity of the new analog was approximately two to four times weaker activity against Gram-positive bacteria, including drug-resistant species, compared with that of tripropeptin C. These results suggest that the L-prolyl-D-proline substructure plays an important role in the observed potency of tripropeptins.

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Acknowledgements

The authors express our special thanks to Mr. Kunio Inoue for the measurement of MICs and to Dr. Tomoyuki Kimura for his valuable discussion. This work was supported by the Japan Society for the Promotion of Science KAKENHI, grant numbers 24710254 and 16K08338. We thank Dr. Renee Mosi, and Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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Authors and Affiliations

  1. Laboratory of Microbiology, Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan

    Hideki Hashizume, Shigeko Harada & Masayuki Igarashi

  2. Laboratory of Molecular Structure Analysis, Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan

    Ryuichi Sawa, Yumiko Kubota & Shinya Adachi

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  1. Hideki Hashizume
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Correspondence to Hideki Hashizume.

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Hashizume, H., Sawa, R., Kubota, Y. et al. Precursor-directed biosynthesis and biological activity of tripropeptin Cpip, a new tripropeptin C analog containing pipecolic acid. J Antibiot 77, 238–244 (2024). https://doi.org/10.1038/s41429-024-00703-9

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