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Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E

Author

Listed:
  • Hiroaki Itoh

    (The University of Tokyo)

  • Kotaro Tokumoto

    (The University of Tokyo)

  • Takuya Kaji

    (The University of Tokyo)

  • Atmika Paudel

    (Teikyo University Institute of Medical Mycology)

  • Suresh Panthee

    (Teikyo University Institute of Medical Mycology)

  • Hiroshi Hamamoto

    (Teikyo University Institute of Medical Mycology)

  • Kazuhisa Sekimizu

    (Teikyo University Institute of Medical Mycology)

  • Masayuki Inoue

    (The University of Tokyo)

Abstract

Lysocin E, a 37-membered natural depsipeptide, induces rapid bacteriolysis in methicillin-resistant Staphylococcus aureus via a unique menaquinone-dependent mechanism, presenting a promising therapeutic lead. Despite the great medical importance, exploring the potential utility of its derivatives as new platform structures for antibiotic development has remained a significant challenge. Here, we report a high-throughput strategy that enabled the preparation of thousands of analogues of lysocin E and large-scale structure-activity relationship analyses. We integrate 26-step total synthesis of 2401 cyclic peptides, tandem mass spectrometry-sequencing, and two microscale activity assays to identify 23 candidate compounds. Re-synthesis of these candidates shows that 11 of them (A1–A11) exhibit antimicrobial activity superior or comparable to that of lysocin E, and that lysocin E and A1–A11 share l-Leu-6 and l-Ile-11. Therefore, the present strategy allows us to efficiently decipher biologically crucial residues and identify potentially useful agents for the treatment of infectious diseases.

Suggested Citation

  • Hiroaki Itoh & Kotaro Tokumoto & Takuya Kaji & Atmika Paudel & Suresh Panthee & Hiroshi Hamamoto & Kazuhisa Sekimizu & Masayuki Inoue, 2019. "Development of a high-throughput strategy for discovery of potent analogues of antibiotic lysocin E," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10754-4
    DOI: 10.1038/s41467-019-10754-4
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    Cited by:

    1. Hiroshi Hamamoto & Suresh Panthee & Atmika Paudel & Kenichi Ishii & Jyunichiro Yasukawa & Jie Su & Atsushi Miyashita & Hiroaki Itoh & Kotaro Tokumoto & Masayuki Inoue & Kazuhisa Sekimizu, 2021. "Serum apolipoprotein A-I potentiates the therapeutic efficacy of lysocin E against Staphylococcus aureus," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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