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Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY

Author

Listed:
  • Takeshi Nakaya

    (Hokkaido University)

  • Miyuki Yabe

    (Hokkaido University)

  • Ellene H. Mashalidis

    (Duke University School of Medicine
    Pfizer Global Research & Development)

  • Toyotaka Sato

    (Hokkaido University
    Hokkaido University)

  • Kazuki Yamamoto

    (Hokkaido University
    Hokkaido University)

  • Yuta Hikiji

    (Hokkaido University)

  • Akira Katsuyama

    (Hokkaido University
    Hokkaido University
    Hokkaido University)

  • Motoko Shinohara

    (Fujita Health University School of Medicine)

  • Yusuke Minato

    (Fujita Health University School of Medicine)

  • Satoshi Takahashi

    (Sapporo Medical University Hospital
    Sapporo Medical University School of Medicine)

  • Motohiro Horiuchi

    (Hokkaido University
    Hokkaido University)

  • Shin-ichi Yokota

    (Sapporo Medical University School of Medicine)

  • Seok-Yong Lee

    (Duke University School of Medicine)

  • Satoshi Ichikawa

    (Hokkaido University
    Hokkaido University
    Hokkaido University)

Abstract

The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.

Suggested Citation

  • Takeshi Nakaya & Miyuki Yabe & Ellene H. Mashalidis & Toyotaka Sato & Kazuki Yamamoto & Yuta Hikiji & Akira Katsuyama & Motoko Shinohara & Yusuke Minato & Satoshi Takahashi & Motohiro Horiuchi & Shin-, 2022. "Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35227-z
    DOI: 10.1038/s41467-022-35227-z
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    References listed on IDEAS

    as
    1. Eric D. Brown & Gerard D. Wright, 2016. "Antibacterial drug discovery in the resistance era," Nature, Nature, vol. 529(7586), pages 336-343, January.
    2. Ben C. Chung & Ellene H. Mashalidis & Tetsuya Tanino & Mijung Kim & Akira Matsuda & Jiyong Hong & Satoshi Ichikawa & Seok-Yong Lee, 2016. "Structural insights into inhibition of lipid I production in bacterial cell wall synthesis," Nature, Nature, vol. 533(7604), pages 557-560, May.
    3. Ellene H. Mashalidis & Benjamin Kaeser & Yuma Terasawa & Akira Katsuyama & Do-Yeon Kwon & Kiyoun Lee & Jiyong Hong & Satoshi Ichikawa & Seok-Yong Lee, 2019. "Chemical logic of MraY inhibition by antibacterial nucleoside natural products," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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    Cited by:

    1. Kazuki Yamamoto & Toyotaka Sato & Aili Hao & Kenta Asao & Rintaro Kaguchi & Shintaro Kusaka & Radhakrishnam Raju Ruddarraju & Daichi Kazamori & Kiki Seo & Satoshi Takahashi & Motohiro Horiuchi & Shin-, 2024. "Development of a natural product optimization strategy for inhibitors against MraY, a promising antibacterial target," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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