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Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa

The Journal of Antibiotics volume 76, pages 691–698 (2023)Cite this article

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Abstract

Pseudomonas aeruginosa is one of the most concerning pathogenic bacteria. We screened antibiotics using a highly drug-sensitive P. aeruginosa strain and an oligotrophic medium, and successfully isolated novel antibiotics, namely cycloimidamicins (CIMs), from a rare actinomycete strain, Lentzea sp. MM249-143F7. X-ray and nuclear magnetic resonance analyses revealed that CIMs possess a distinctive and unprecedented molecular structure, containing tetramic acid and an imidazole ring bound directly to indolone. The CIMs exhibited potent antibacterial activity against Gram-negative bacteria, as well as translation inhibition in Escherichia coli in both intact cells and in vitro. Additionally, E. coli strains resistant to known translation inhibitors did not exhibit cross-resistance to CIMs, suggesting that CIMs inhibit bacterial growth by blocking translation through a novel mechanism.

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Acknowledgements

This work was partially supported by the Japan Agency for Medical Research and Development (AMED) program (Grant No. JP19fk0108093) to MI, and the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI, Grant No. 23K06191) to YI. We are grateful to the National BioResource Project: E. coli, National Institute of Genetics, Japan for providing the E. coli CAG12184. We thank Ms. Sayaka Takahashi for technical assistance in the mode of action study and Dr. Shinya Adachi for measurement of mass spectra. We thank Dr. Barbara Garbers from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

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

    Yoshimasa Ishizaki, Maya Umekita, Rie Arisaka, Masaki Hatano, Tomoyuki Kimura, Yumiko Kubota, Yuko Shibuya, Chigusa Hayashi, Ryuichi Sawa & Masayuki Igarashi

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  1. Yoshimasa Ishizaki
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  2. Maya Umekita
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Correspondence to Masayuki Igarashi.

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Ishizaki, Y., Umekita, M., Arisaka, R. et al. Cycloimidamicins, Novel natural lead compounds for translation inhibition in Pseudomonas aeruginosa. J Antibiot 76, 691–698 (2023). https://doi.org/10.1038/s41429-023-00656-5

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