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Development of irreversible inhibitors forβ-lactam inactived enzyme, metallo-β-lactamase

Research Project

Project/Area Number 21590116
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Drug development chemistry
Research InstitutionKumamoto University

Principal Investigator

KUROSAKI Hiromasa  熊本大学, 大学院・生命科学研究部, 准教授 (70234599)

Co-Investigator(Kenkyū-buntansha) YAMAGUCHI Yoshihiro  熊本大学, 環境安全センター, 准教授 (10363524)
Co-Investigator(Renkei-kenkyūsha) ARAKAWA Yoshichika  名古屋大学, 大学院・医学系研究科, 教授 (10212622)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords医薬分子設計 / 感染症 / β-ラクタム剤 / 薬剤耐性菌 / 阻害剤 / 金属酵素 / 薬学 / 抗生物質 / 耐性菌 / 細菌 / 酵素
Research Abstract

IMP-1 metallo-β-lactamase is a dinuclear Zn(II) enzyme that catalyzes the hydrolysis and inactivation of mostβ-lactams including carbapenems, and is involved in one of the mechanisms for generating clinical resistance to antibiotics in pathogenic bacteria. We investigated the metal preferences of Zn(II) and Co(II) for the apo-enzyme of IMP-1 metallo-β-lactamase, apo-IMP-1, which contains a dinuclear metal binding site(the Zn1 and Zn2 sites), by UV-visible spectroscopy. The UV-visible spectrum of apo-IMP-1 containing 1 equiv. of Co(II) and 1 equiv. of Zn(II) showed a high preference of Zn(II) for the Zn1 site compared to Co(II). The interaction of IMP-1 metallo-β-lactamase with mercaptoacetic acid was also investigated using Co(II)-substituted IMP-1 and UV-visible spectroscopy. Possible metal binding modes of Co(II) or Zn(II) to the dinucelar metal binding site in apo-IMP-1 and of mercaptoacetic acid to Co(II)-substituted IMP-1 are proposed.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (8 results)

All 2011 2010 2009

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (4 results)

  • [Journal Article] A demetallation method for IMP-1 metallo-β-lactamase that restored enzymatic activity upon addition of metal ion(s)2011

    • Author(s)
      Yoshihiro Yamaguchi, Shijia Ding, Emi Murakami, Kayo Imamura, Sachiko Fuchigami, Ryo Hashiguchi, Katsuhide Yutani, Hiromasa Mori, Shinnichiro Suzuki, Yoshichika Arakawa, Hiromasa Kurosaki
    • Journal Title

      ChemBioChem

      Volume: 12(13) Pages: 1979-1983

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Metal preference of Zn(II) and Co(II) for the dinuclear metal binding site of IMP-1 metallo-β-lactamase and spectroscopic properties of Co(II)-substituted IMP-1 with mercaptoacetic acid2011

    • Author(s)
      Yoshihiro Yamaguchi, Kayo Imamura, Ako Sasao, Emi Murakami, Yoshichika Arakawa, Hiromasa Kurosaki
    • Journal Title

      Med. Chem. Commun

      Volume: 2(8) Pages: 720-725

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] A demetallation method for IMP-1 metallo-ss-lactamase with restored enzymatic activity upon addition of metal ion(s)2011

    • Author(s)
      Yamaguchi Y, Ding S, Murakami E, Imamura K, Fuchigami S, Hashiguchi R, Yutani K, Mori H, Suzuki S, Arakawa Y, Kurosaki H
    • Journal Title

      ChemBioChem

      Volume: 12 Issue: 13 Pages: 1979-1983

    • DOI

      10.1002/cbic.201100342

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Metal preference of Zn(II) and Co(II) for the dinuclear metal binding site of IMP-1 metallo-β-lactamase and spectroscopic properties of Co(II)-substituted IMP-1 with mercaptoacetic acid2011

    • Author(s)
      Yamaguchi Y, Imamura K, Sasao A, Murakami E, Arakawa Y, Kurosaki H
    • Journal Title

      Med.Chem.Commun.

      Volume: 2 Issue: 8 Pages: 720-725

    • DOI

      10.1039/c1md00062d

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Detection of metallo-β-lactamase producing bacteria by fluoresent probe having dansyl and thiol groups2010

    • Author(s)
      Kouki Matsuda, Yoshihiro Yamaguchi, Junzo Hirose, Yoshichika Arakawa, Hiromasa Kurosaki
    • Organizer
      第20回金属の関与する生体関連反応シンポジウム
    • Place of Presentation
      徳島文理大学(徳島)
    • Year and Date
      2010-06-25
    • Related Report
      2011 Final Research Report
  • [Presentation] etection of metallo-β-lactamase producing bacteria by fluorescent probe having dansyl and thiol groups2010

    • Author(s)
      Koki MATSUDA, Yoshihiro YAMAGUCHI, Junzo HIROSE, Yoshichika ARAKAWA, Hiromasa KUROSAKI
    • Organizer
      第20回金属の関与する生体関連反応シンポジウム
    • Place of Presentation
      徳島文理大学(徳島)
    • Related Report
      2010 Annual Research Report
  • [Presentation] 薬剤耐性菌が産生するメタロ-β-ラクタマーゼの蛍光検出法の開発:ダンシルとチオール基を持つ蛍光剤のメタロ-β-ラクタマーゼIMP-1, VIM-2, IND-7に対する蛍光特性と速度論解析2009

    • Author(s)
      松田幸喜、山口佳宏、廣瀬順三、荒川宜親、黒崎博雅
    • Organizer
      第38回薬剤耐性菌研究会
    • Place of Presentation
      森秋旅館(群馬)
    • Year and Date
      2009-11-20
    • Related Report
      2011 Final Research Report
  • [Presentation] 薬剤耐性菌が産生するメタロ-β-ラクタマーゼの蛍光検出法の開発:ダンシル基とチオール基をもつ蛍光剤のメタロ-β-ラクタマーゼIMP-1, VIM-2, IMD-7に対する蛍光特性と速度論的解析2009

    • Author(s)
      松田幸喜, 山口佳宏, 廣瀬順造, 荒川宜親, 黒崎博雅
    • Organizer
      第38回薬剤耐性菌研究会
    • Place of Presentation
      森秋旅館(群馬県)
    • Year and Date
      2009-11-20
    • Related Report
      2009 Annual Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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