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Structural studies on antibiotic-resistance mechanisms and their application to drug design

Research Project

Project/Area Number 23790054
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Physical pharmacy
Research InstitutionSophia University

Principal Investigator

KONDO Jiro  上智大学, 理工学部, 助教 (10546576)

Research Collaborator HANESSIAN Stephen  モントリオール大学, 教授
BAASOV Timor  テクニオン工科大学, 教授
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywords薬剤耐性菌 / 抗生物質 / リボソーム / X線結晶解析 / ドラッグデザイン / X線結晶解析
Research Abstract

Aminoglycosides are broad spectrum antibiotics acting against a variety of Gram-negative and certain Gram-positive bacteria. Aminoglycosides specifically bind to one of the active sites of the bacterial ribosome called the A site, and disturb the fidelity of the decoding process in protein synthesis. Bacteria acquire high-level resistance against aminoglycosides by mutating the position 1408 of the ribosomal RNA A site, from A to G or 1-methyl-A. In the present study, we have performed X-ray analyses of the ribosomal RNA A sites with these antibiotic-resistant mutations and revealed structural bases for the antibiotic resistance conferred by the point mutatations. In addition, we have successfully designed and synthesized a new compound with high activity against antibiotic-resistant bacteria and parasitic protozoa.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (40 results)

All 2014 2013 2012 2011 Other

All Journal Article (9 results) (of which Peer Reviewed: 5 results) Presentation (24 results) (of which Invited: 1 results) Book (2 results) Remarks (5 results)

  • [Journal Article] Identification of the molecular attributes required for aminoglycoside activity against Leishmania2013

    • Author(s)
      Moran Shalev, Jiro Kondo, Dmitry Kopelyanskiy, Charles L. Jaffe, Noam Adir, Timor Baasov
    • Journal Title

      Proc. Natl. Acad. Sci. USA

      Volume: 110 Issue: 33 Pages: 13333-1338

    • DOI

      10.1073/pnas.1307365110

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Crystal structures of a bioactive 6'-hydroxy variant of sisomicin bound to the bacterial and protozoal ribosomal decoding sites2013

    • Author(s)
      Jiro Kondo, Mai Koganei, Juan Pablo Maianti,Vu Linh Ly, Stephen Hanessian
    • Journal Title

      ChemMedChem

      Volume: 8 Issue: 5 Pages: 733-739

    • DOI

      10.1002/cmdc.201200579

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] リボソームの分子進化 : AサイトRNA分子スイッチの動きからの考察2013

    • Author(s)
      近藤次郎
    • Journal Title

      実験医学増刊号

      Volume: 31 Pages: 1011-1017

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Crystal structures of the bacterial and protozoal A sites in complex with 6'-hydroxysisomicin2013

    • Author(s)
      Jiro Kondo, Mai Koganei, Juan Pablo Maianti, Vu Linh Ly, Stephen Hanessian
    • Journal Title

      Photon Factory Activity Report 2012

      Volume: 30 Pages: 285-285

    • Related Report
      2013 Annual Research Report
  • [Journal Article] Crystal structures of the bacterial A site in complex with sisomicin2013

    • Author(s)
      Jiro Kondo, Mai Koganei, Tomoko Kasahara
    • Journal Title

      Photon Factory Activity Report 2012

      Volume: 30 Pages: 286-286

    • Related Report
      2013 Annual Research Report
  • [Journal Article] リボソームの分子進化:AサイトRNA分子スイッチの動きからの考察2013

    • Author(s)
      近藤次郎
    • Journal Title

      実験医学増刊号

      Volume: 31 Pages: 1011-1017

    • Related Report
      2012 Research-status Report
  • [Journal Article] Crystal structure and specific binding mode of sisomicin to the bacterial ribosomal decoding site2012

    • Author(s)
      Jiro Kondo, Mai Koganei, Tomoko Kasahara
    • Journal Title

      ACS Medicinal Chemistry Letters

      Volume: 3 Issue: 9 Pages: 741-744

    • DOI

      10.1021/ml300145y

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA and for the antiprotozoal activity of aminoglycosides2012

    • Author(s)
      Jiro Kondo
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 51 Issue: 2 Pages: 465-468

    • DOI

      10.1002/anie.201106084

    • Related Report
      2013 Final Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Crystal structures of the bacterial A1408G-mutant A site with and without geneticin2012

    • Author(s)
      Jiro Kondo
    • Journal Title

      Photon Factory Activity Report 2011

      Volume: 29 Pages: 339-339

    • Related Report
      2012 Research-status Report
  • [Presentation] ストロンチウムイオン結合モチーフを持つ特殊なRNA二重らせんの立体構造2014

    • Author(s)
      金澤宏樹、近藤次郎
    • Organizer
      物構研サイエンスフェスタ2013
    • Place of Presentation
      つくば国際会議場エポカル(つくば市)
    • Related Report
      2013 Final Research Report
  • [Presentation] ストロンチウムイオン結合モチーフを持つ特殊なRNA二重らせんの立体構造2014

    • Author(s)
      金澤宏樹、近藤次郎
    • Organizer
      物構研サイエンスフェスタ2013
    • Place of Presentation
      つくば国際会議場エポカル(つくば市)
    • Related Report
      2013 Annual Research Report
  • [Presentation] ヒト・ミトコンドリアリボソームRNAの結晶多形性と立体構造との相関2013

    • Author(s)
      宮崎まい、鉄本環、高橋由紀子、近藤次郎
    • Organizer
      平成25年度日本結晶学会年会
    • Place of Presentation
      熊本大学(熊本市)
    • Related Report
      2013 Final Research Report
  • [Presentation] Crystal structures of the protozoal cytoplasmic A site in complex with aminoglycosides. RNA20132013

    • Author(s)
      Jiro Kondo, Mai Koganei
    • Organizer
      18th annual meeting of the RNA society
    • Place of Presentation
      スイス・ダボス
    • Related Report
      2013 Final Research Report
  • [Presentation] Crystal structures of the protozoal cytoplasmic A site in complex with aminoglycosides2013

    • Author(s)
      Jiro Kondo, Mai Koganei
    • Organizer
      RNA2013 (18th annual meeting of the RNA society)
    • Place of Presentation
      スイス・ダボス
    • Related Report
      2013 Annual Research Report
  • [Presentation] ヒト・ミトコンドリアリボソームRNA の結晶多形性と立体構造との相関2013

    • Author(s)
      宮崎まい、鉄本環、高橋由紀子、近藤次郎
    • Organizer
      平成25年度日本結晶学会年会
    • Place of Presentation
      熊本大学(熊本市)
    • Related Report
      2013 Annual Research Report
  • [Presentation] X線結晶解析で見るRNA分子スイッチの「動き」=「働き」2012

    • Author(s)
      近藤次郎
    • Organizer
      第63回結晶化学研究会
    • Place of Presentation
      東京工業大学(東京都)
    • Year and Date
      2012-12-22
    • Related Report
      2013 Final Research Report
  • [Presentation] Towards the structure-based design of antiprozoal agents : crystal structures of aminoglycosides with an unsaturated sugar ring bound to the ribosomal A sites. ISNAC20122012

    • Author(s)
      Jiro Kondo, Mai Koganei, Tomoko Kasahara, Stephen Hanessian
    • Organizer
      The 39th International Symposium on Nucleic Acid Chemistry
    • Place of Presentation
      名古屋大学(名古屋市)
    • Related Report
      2013 Final Research Report
  • [Presentation] アミノグリコシド系抗生物質に対する薬剤耐性獲得メカニズムの構造基盤2012

    • Author(s)
      近藤次郎
    • Organizer
      平成24年度日本結晶学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2013 Final Research Report
  • [Presentation] A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA2012

    • Author(s)
      Jiro Kondo
    • Organizer
      The 50th Annual Meeting of the Biophysical Society of Japan
    • Place of Presentation
      名古屋大学(名古屋市)
    • Related Report
      2013 Final Research Report
  • [Presentation] 16S rRNAのA1408G変異による薬剤耐性獲得の構造基盤2012

    • Author(s)
      近藤次郎
    • Organizer
      第14回日本RNA学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2013 Final Research Report
  • [Presentation] 細菌リボソームAサイト-シソマイシン複合体の結晶構造2012

    • Author(s)
      小金井麻衣、笠原朋子、近藤次郎
    • Organizer
      第14回日本RNA学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2013 Final Research Report
  • [Presentation] 細菌リボソームAサイト-シソマイシン複合体のX線結晶解析2012

    • Author(s)
      小金井麻衣、笠原朋子、近藤次郎
    • Organizer
      第1回リボソームミーティング
    • Place of Presentation
      広島大学(東広島市)
    • Related Report
      2013 Final Research Report
  • [Presentation] アミノグリコシド系抗生物質に対する耐性獲得メカニズムの構造基盤2012

    • Author(s)
      近藤次郎
    • Organizer
      第1回リボソームミーティング
    • Place of Presentation
      広島大学(東広島市)
    • Related Report
      2013 Final Research Report
  • [Presentation] 細菌リボソームAサイト-シソマイシン複合体の結晶構造2012

    • Author(s)
      小金井麻衣、笠原朋子、近藤次郎
    • Organizer
      第14回日本RNA学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2012 Research-status Report
  • [Presentation] 16S rRNAのA1408G変異による薬剤耐性獲得の構造基盤2012

    • Author(s)
      近藤次郎
    • Organizer
      第14回日本RNA学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2012 Research-status Report
  • [Presentation] A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA2012

    • Author(s)
      Jiro Kondo
    • Organizer
      The 50th Annual Meeting of the Biophysical Society of Japan
    • Place of Presentation
      名古屋大学(名古屋市)
    • Related Report
      2012 Research-status Report
  • [Presentation] アミノグリコシド系抗生物質に対する薬剤耐性獲得メカニズムの構造基盤2012

    • Author(s)
      近藤次郎
    • Organizer
      平成24年度日本結晶学会年会
    • Place of Presentation
      東北大学(仙台市)
    • Related Report
      2012 Research-status Report
  • [Presentation] Towards the structure-based design of antiprozoal agents: crystal structures of aminoglycosides with an unsaturated sugar ring bound to the ribosomal A sites2012

    • Author(s)
      Jiro Kondo, Mai Koganei, Tomoko Kasahara, Stephen Hanessian
    • Organizer
      ISNAC2012 (The 39th International Symposium on Nucleic Acid Chemistry)
    • Place of Presentation
      名古屋大学(名古屋市)
    • Related Report
      2012 Research-status Report
  • [Presentation] X線結晶解析で見るRNA分子スイッチの「動き」=「働き」2012

    • Author(s)
      近藤次郎
    • Organizer
      第63回結晶化学研究会
    • Place of Presentation
      東京工業大学(東京都)
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] アミノグリコシド系抗生物質に対する耐性獲得メカニズムの構造基盤2012

    • Author(s)
      近藤 次郎
    • Organizer
      第1回リボソームミーティング
    • Place of Presentation
      広島大学(東広島市)
    • Related Report
      2011 Research-status Report
  • [Presentation] 細菌リボソームAサイト-シソマイシン複合体のX線結晶解析2012

    • Author(s)
      小金井 麻衣、笠原 朋子、近藤 次郎
    • Organizer
      第1回リボソームミーティング
    • Place of Presentation
      広島大学(東広島市)
    • Related Report
      2011 Research-status Report
  • [Presentation] Structural basis for antibiotic resistance conferred by an A1408G mutation in 16S rRNA, ISNAC20112011

    • Author(s)
      Jiro Kondo
    • Organizer
      The 38th International Symposium on Nucleic Acid Chemistry
    • Place of Presentation
      北海道大学(札幌市)
    • Related Report
      2013 Final Research Report
  • [Presentation] Structural basis for antibiotic resistance conferred by an A1408G mutation in 16S rRNA2011

    • Author(s)
      Jiro Kondo
    • Organizer
      ISNAC2011 (The 38th International Symposium on Nucleic Acid Chemistry)
    • Place of Presentation
      北海道大学(札幌市)
    • Related Report
      2011 Research-status Report
  • [Book] Claude Sauter & Benoît Masquida. RNA crystallization. In Roland K. Hartmann, Albrecht Bindereif, Astrid Schon & Eric Westhof (eds.), Handbook of RNA Biochemistry, second edition2014

    • Author(s)
      Jiro Kondo
    • Publisher
      Wiley VHC
    • Related Report
      2013 Final Research Report
  • [Book] structural decoding of inhibitors targeting the ribosomal decoding A site. In Claudio O. Gualerzi, Letizia Brandi, Attilio Fabbretti & Cynthia L. Pon (eds.), Antibiotics : Targets, Mechanisms and Resistance2013

    • Author(s)
      Jiro Kondo & Eric Westhof
    • Publisher
      Wiley VHC
    • Related Report
      2013 Final Research Report
  • [Remarks] Biotechdaily - Online bioresearch news - 2013年8月20日 Light shed on differential effectiveness of aminoglycosides against parasitic protozoa

    • Related Report
      2013 Final Research Report
  • [Remarks] 化学工業日報 2011年12月12日 「上智大 細菌の抗生物質耐性獲得メカニズム解明 新薬の設計・開発に応用も」

    • Related Report
      2013 Final Research Report
  • [Remarks] 上智大学プレスリリース 2011年12月5日 「細菌のアミノグリコシド系抗生物質に対する耐性メカニズムを分子レベルで解明~耐性菌が抗生物質を免れる分子メカニズムを世界で初めて明らかに~」

    • URL

      https://www.sophia.ac.jp/jpn/content/download/22110/.../file/111205press.pdf

    • Related Report
      2013 Final Research Report
  • [Remarks]

    • URL

      http://www.sophia.ac.jp/jpn/content/download/22110/215757/file/111205press.pdf

    • Related Report
      2011 Research-status Report
  • [Remarks]

    • URL

      http://www.st.sophia.ac.jp/wordpress/?p=274

    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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