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Structure-based discovery of metallo-type carbapenemase inhibitor and application to bacteriological examination

Research Project

Project/Area Number 24790570
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Laboratory medicine
Research InstitutionNagoya University

Principal Investigator

WACHINO Jun-ichi  名古屋大学, 医学(系)研究科(研究院), 助教 (00535651)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords薬剤耐性菌 / メタロβ-ラクタマーゼ / カルバペネム耐性 / メタロ-β-ラクタマーゼ / SMB-1 / D-captopril / 薬剤耐性
Outline of Final Research Achievements

We determined the crystal structure of SMB-1 using 1.6A diffraction data, and revealed that the overall structure of SMB-1 was quite similar to those of the other subclass B3 MBLs, AIM-1, L1, and BJP-1. The electron density map corresponding to a water molecule (wat1), which is assumed to contribute as the attacking nucleophile on the carbonyl carbon of the beta-lactam ring, was observed. SMB-1 possesses a unique amino acid residue, Q157, which probably plays a role in recognition of beta-lactams via the hydrogen bond interaction. In addition, we determined the mercaptoacetate (MCR)-complexed SMB-1 structure and revealed that the mode of its inhibition by MCR: the thiolate group bridges to two zinc ions (Zn1 and Zn2), and occupy the space to which beta-lactams originally bind. Finally, we performed in silico screening to find effective inhibitors of SMB-1 and found four agents which could behave as inhibitors of SMB-1.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (19 results)

All 2015 2014 2013 2012

All Journal Article (11 results) (of which Peer Reviewed: 11 results) Presentation (7 results) (of which Invited: 3 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Invasive infection caused by carbapenem-resistant Acinetobacter soli, Japan.2014

    • Author(s)
      Kitanaka H, Sasano MA, Yokoyama S, Suzuki M, Jin W, Inayoshi M, Hori M, Wachino J, Kimura K, Yamada K, Arakawa Y.
    • Journal Title

      Emerg Infect Dis

      Volume: 20 Issue: 9 Pages: 1574-6

    • DOI

      10.3201/eid2009.140117

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel integron-mediated fosfomycin resistance gene fosK2014

    • Author(s)
      Kitanaka H, Wachino J, Jin W, Yokoyama S, Sasano MA, Hori M, Yamada K, Kimura K, Arakawa Y
    • Journal Title

      Antimicrob Agents Chemother

      Volume: 58 Issue: 8 Pages: 4978-9

    • DOI

      10.1128/aac.03131-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Practical Agar-Based Disk Potentiation Test to Detect Fosfomycin-Non-Susceptible Escherichia coli Clinical Isolates Producing Glutathione S-Transferases2014

    • Author(s)
      G. Nakamura, J. Wachino, N. Sato, K. Kimura, K. Yamada, W. Jin, K. Shibayama, T. Yagi, K. Kawamura, Y. Arakawa
    • Journal Title

      Journal Clinical Microbiology

      Volume: 52 Issue: 9 Pages: 3175-3179

    • DOI

      10.1128/jcm.01094-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of Disk Potentiation Test Using KB Disks Containing High Dosage Fosfomycin and Glucose-6-Phosphate to Detect the Production of Glutathione S-Transferase Responsible For Fosfomycin Resistance2014

    • Author(s)
      J. Wachino, K. Kimura, K. Yamada, W. Jin, Y. Arakawa
    • Journal Title

      Journal Clinical Microbiology

      Volume: 52 Issue: 10 Pages: 3827-3828

    • DOI

      10.1128/jcm.01805-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of a double-disk synergy test with a common metallo-β-lactamase inhibitor, mercaptoacetate, for detecting NDM-1-producing Enterobacteriaceae and Acinetobacter baumannii2014

    • Author(s)
      Wachino J, Matsui M, Tran HH, Suzuki M, Suzuki S, Shibayama K
    • Journal Title

      Japanese Journal of Infectious Diseases

      Volume: 67 Pages: 66-68

    • NAID

      130003399237

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Rapid and reliable loop-mediated isothermal amplification method for detecting Streptococcus agalactiae2013

    • Author(s)
      Kimura K, Yanagisawa H, Wachino J, Shibayama K, Arakawa Y
    • Journal Title

      Japanese Journal of Infectious Diseases

      Volume: 66 Pages: 546-548

    • NAID

      130003390340

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] First detection of fosfomycin resistance gene fosA3 in CTX-M-producing Escherichia coli isolates from healthy individuals in Japan2013

    • Author(s)
      Sato N, Kawamura K, Nakane K, Wachino J, Arakawa Y
    • Journal Title

      Microbial Drug Resistance

      Volume: 19 Issue: 6 Pages: 477-482

    • DOI

      10.1089/mdr.2013.0061

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Screening for group B streptococci with reduced penicillin susceptibility in clinical isolates obtained between 1977 and 20052013

    • Author(s)
      Kimura K, Nishiyama Y, Shimizu S, Wachino J, Matsui M, Suzuki S, Yamane K, Shibayama K, Arakawa Y
    • Journal Title

      Japanese Journal of Infectious Diseases

      Volume: 66 Pages: 222-225

    • NAID

      130003381675

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] High cephalosporin resistance due to amino acid substitutions in PBP1A and PBP2X in a clinical isolate of group B Streptococcus2013

    • Author(s)
      Kimura K, Wachino J, Kurokawa H, Matsui M, Suzuki S, Yamane K, Nagano N, Shibayama K, Arakawa Y.
    • Journal Title

      Journal of Antimicrobial Chemotherapy

      Volume: 68 Issue: 7 Pages: 1533-1536

    • DOI

      10.1093/jac/dkt060

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Ability of the VITEK(R) 2 system to detect group B streptococci with reduced penicillin susceptibility (PRGBS)2013

    • Author(s)
      Kimura K, Nagano N, Nagano Y, Wachino J, Shibayama K, Arakawa Y.
    • Journal Title

      Journal of Antimicrobial Chemotherapy

      Volume: 68 Pages: 1442-1444

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate2012

    • Author(s)
      Jun-ichi Wachino, Yoshihiro Yamaguchi, Shigetarou Mori, Hiromasa Kurosaki, Yoshichika Arakawa, Keigo Shibayama
    • Journal Title

      Antimicrob. Agents Chemother.

      Volume: 57 Issue: 1 Pages: 101-109

    • DOI

      10.1128/aac.01264-12

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] CREが産生するカルバペネマーゼの種類と CREの疫学2015

    • Author(s)
      和知野純一、荒川宜親
    • Organizer
      第26回日本臨床微生物学会総会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Year and Date
      2015-02-01 – 2015-02-02
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] ESBL産生大腸菌における新型ホスホマイシン 耐性機構の出現とその簡易識別法の開発2014

    • Author(s)
      和知野純一、木村幸司、荒川宜親
    • Organizer
      第61日本化学療法学会東日本支部総会
    • Place of Presentation
      東京ドームホテル(東京都文京区)
    • Year and Date
      2014-10-29 – 2014-10-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] メルカプト酢酸ナトリウム(SMA)を用いたNDM型メタロβ-ラクタマーゼ産生株検出法の評価2014

    • Author(s)
      和知野純一、荒川宜親
    • Organizer
      第62回日本化学療法学会総会
    • Place of Presentation
      ヒルトン福岡シーホーク(福岡市)
    • Year and Date
      2014-06-18 – 2014-06-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] 多剤耐性を引き起こすカルバペネマーゼに関する最新の知見2013

    • Author(s)
      和知野純一、荒川宜親
    • Organizer
      第61回日本化学療法学会西日本支部総会
    • Place of Presentation
      大阪国際会議場(大阪市)
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] アミノグリコシド、フルオロキノロン、ホスホマイシン耐性メカニズムの新知見2013

    • Author(s)
      和知野純一、荒川宜親
    • Organizer
      第61回日本化学療法学会総会
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] Genetic, biochemical and structural analyses of a subclass B3 metallo-β-lactamase SMB-1 from a Serratia marcescens clinical isolate2013

    • Author(s)
      Jun-ichi Wachino, Yoshichika Arakawa
    • Organizer
      28th International Congress of Chemotherapy and Infection
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Related Report
      2013 Research-status Report
  • [Presentation] メタロ-β-ラクタマーゼSMB-1の構造機能解析2013

    • Author(s)
      和知野純一、森茂太郎、柴山恵吾、荒川宜親
    • Organizer
      第86回日本細菌学会総会
    • Place of Presentation
      千葉市
    • Related Report
      2012 Research-status Report
  • [Patent(Industrial Property Rights)] ホスホマイシン不活化酵素産生菌の検出2014

    • Inventor(s)
      和知野純一、荒川宜親
    • Industrial Property Rights Holder
      名古屋大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2014-04-15
    • Related Report
      2014 Annual Research Report

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Published: 2013-05-31   Modified: 2019-07-29  

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