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Producing the luminamicin analogs by genetic engineering

Research Project

Project/Area Number 20K07105
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47050:Environmental and natural pharmaceutical resources-related
Research InstitutionKitasato University

Principal Investigator

Inahashi Yuki  北里大学, 感染制御科学府, 准教授 (70645522)

Co-Investigator(Kenkyū-buntansha) 廣瀬 友靖  北里大学, 感染制御科学府, 教授 (00370156)
松井 秀仁  北里大学, 大村智記念研究所, 講師 (80503797)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsルミナミシン / Clostridioides difficile / 生合成 / 放線菌 / C. difficile / 誘導体合成 / 抗嫌気性細菌
Outline of Research at the Start

ルミナミシンは放線菌Streptomyces sp. OMR-59の培養液より発見された強力かつ選択性に優れた抗C. difficile活性物質である。その構造には、無水マレイン酸含有14員環ラクトン(ノーザンパート)とシスデカリン含有10員環ラクトン(サザンパート)が結合した複雑でユニークな骨格を有する。本研究では、新規CDI治療薬の創製を目標に、「ルミナミシンの生合成におけるノーザンパートとサザンパートのカップリング反応の解明」および「生合成遺伝子改変と有機合成による非天然型ルミナミシン誘導体合成」を目指す。

Outline of Final Research Achievements

The biosynthetic gene cluster of luminamicin, an anti C. difficile agent, was predicted from the genome sequence of OMR-59. The deletion mutant of each gene, which may involve the coupling of the northern and southern parts, was generated. The LC/UV analysis of the metabolites indicated that those genes were important for the biosynthesis. Furthermore, the intermediates (or shunt products) of luminamicin biosynthesis were isolated from the culture broths. We evaluated the antibiotic activity of those compounds against C. difficile, but they did not have the activity. This result gave the information of structure and activity relationship.

Academic Significance and Societal Importance of the Research Achievements

ルミナミシンは放線菌Streptomyces sp. OMR-59の培養液より発見された強力かつ選択性に優れた抗C. difficile活性物質である。本研究よりルミナミシンの生合成遺伝子クラスターが特定され、いくつかの遺伝子についてその機能が推定された。また、取得されたルミナミシン類縁体より僅かではあるが構造活性相関の情報が得られた。今後、本研究より得られた結果を基に、遺伝子組換え株からの類縁体取得やその誘導化を行い、より活性の強いルミナミシン類縁体の取得が期待される。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (2 results)

All 2022 2021

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results) Presentation (1 results)

  • [Journal Article] A Chemical Degradation-Inspired Total Synthesis of the Antibiotic Macrodiolide, Luminamicin2022

    • Author(s)
      Aoi Kimishima, Hiroyasu Ando, Goh Sennari, Yoshihiko Noguchi, Shogo Sekikawa, Toru Kojima, Motoyoshi Ohara, Yoshihiro Watanabe, Yuki Inahashi, Hirokazu Takada, Akihiro Sugawara, Takanori Matsumaru, Masato Iwatsuki, Tomoyasu Hirose, Toshiaki Sunazuka
    • Journal Title

      J. Am. Chem. Soc.

      Volume: 144 Issue: 50 Pages: 23148-23157

    • DOI

      10.1021/jacs.2c10856

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] 無水マレイン酸とポリケタイド骨格を特徴としたluminamicinの生合成研究2021

    • Author(s)
      石井皓大, 小牧彩乃, 関川章悟, 小嶋透, 堤隼馬, 廣瀬友靖, 砂塚敏明, 稲橋 佑起
    • Organizer
      2021年度日本放線菌学会大会
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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