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バクテリアの代替的呼吸酵素の新規阻害剤の探索とその生化学的・医学的展開

Research Project

Project/Area Number 20570124
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionThe University of Tokyo

Principal Investigator

茂木 立志  The University of Tokyo, 医学(系)研究科(研究院), その他 (90219965)

Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2010: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2008: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Keywords感染症 / 天然抗生物質ライブラリー / 呼吸酵素 / 阻害剤 / スクリーニング / ミトコンドリア / 多剤耐性菌 / 抗菌剤
Research Abstract

薬剤耐性菌による感染症の治療を目指し、従来の抗生物質と異なる標的・作用機構をもつ薬剤としてヒトミトコンドリアには存在しない呼吸酵素の阻害剤を同定するため、天然抗生物質ライブラリーのスクリーニングを行った。1)酢酸菌のシアン耐性キノール酸化酵素の分光学的および酵素学的性質を解明し、キノール結合部位阻害剤としてアンチマイシンA、グラミシジンS、LL-Z1272γ、オーラシンCおよびD、ピエリシジンAを同定した。2)緑膿菌の呼吸鎖電子伝達系酵素のスクリーニングから、病原体のコハク酸脱水素酵素のキノン結合部位に働く阻害剤としてシッカニンを同定した。3)結核菌のモデル系であるMycobacterium smegmatisでは、NADH脱水素酵素NDH-IIおよびリンゴ酸:キノン酸化還元酵素のキノン結合部位阻害剤としてポリミキシンBとE、ナナオマイシンAを同定した。新規抗生物質の標的候補でバクテリアに固有な呼吸酵素であるシトクロムbd型およびbo型キノール酸化酵素の反応中心の構造と働きを部位特異的変異体や物理化学的手法を利用して明らかにした。蛋白構造の面から新規抗生物質を同定するために呼吸鎖オキシダーゼの酸素還元部位に用いられるヘムOやAを供給する生合成酵素の発現・精製系を確立し、反応中心の構造を検討した。更に、ミトコンドリアの代謝系酵素のバインオインフォーマティクス解析から、マラリ原虫のATP合成酵素とコハク酸脱水素酵素の膜アンカーサブユニットを同定し、Cryptosporidiumミトコンドリアの種間多様性を明らかにした。本研究は天然抗生物質の迅速なマトリックススクリーニングや構造生物学的研究によって種特異的な細菌呼吸酵素阻害剤を同定できること、これらをリード化合物として新規の感染症薬を開発できる可能性を示した。

Report

(2 results)
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (37 results)

All 2010 2009 2008

All Journal Article (22 results) (of which Peer Reviewed: 22 results) Presentation (15 results)

  • [Journal Article] Diversity in mitochondrial metabolic pathways in parasitic protists Plasmodium and Cryptosporidium2010

    • Author(s)
      茂木立志
    • Journal Title

      Parasitol.Int. 59(印刷中(掲載確定))

    • NAID

      10029824699

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of replacement of low-spin heme b by heme O on Escherichia coli cytochrome bo and bd quinol oxidases2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 145

      Pages: 599-607

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Probing structure of heme A synthase from Bacillus subtilis by site-directed mutagenesis2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 145

      Pages: 625-633

    • NAID

      10025588969

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overexpression and characterization of Bacillus subtilis heme O synthase2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 145

      Pages: 669-675

    • NAID

      10025589144

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Intramolecular electron transfer processes in Cu_B-deficient cytochrome bo studied by pulse radiolysis2009

    • Author(s)
      Kobayashi, K., Mogi, T., 3名中3番目
    • Journal Title

      J.Biochem. 145

      Pages: 686-691

    • NAID

      10025589226

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Probing the heme d-binding site in cytochrome bd quinol oxidase by site-directed mutagenesis2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 145

      Pages: 763-770

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biochemical and spectroscopic properties of cyanide-insensitive quinoloxidase from Gluconobacter oxydans2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochim. 146

      Pages: 263-271

    • NAID

      10026302925

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel mitochondrial Complex II isolated from Trypanosoma crruzi is composed of twelve peptides including a heterodimeric Ip subunit2009

    • Author(s)
      Morales, J., 茂木立志, 9名中2番目
    • Journal Title

      J.Biol.Chem. 284

      Pages: 7255-7263

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Electron transfer processes in subunit I mutants of cytochrome bo quinol oxidase from Escherichia coli2009

    • Author(s)
      Kobayashi, K., 茂木立志, 3名中3番目
    • Journal Title

      Biosci.Biotech.Biochem. 73

      Pages: 1599-1603

    • NAID

      10027543657

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heme/heme redox interaction and resolution of individual optical absorption spectra of the hemes in cytochrome bd from Escherichia coli2009

    • Author(s)
      Bloch, D.A., 茂木立志, 4名中3番目
    • Journal Title

      Biochim.Biophys.Acta 1787

      Pages: 1246-1253

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Siccanin rediscovered as a species-selective succinate dehydrogenase inhibitor2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 146

      Pages: 383-387

    • NAID

      10026303339

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polymyxin B identified as an inhibitor of alternative NADH dehydrogenase and malate : quinone oxidoreductase from the Gram-positive bacterium Mycobacterium smegmatis2009

    • Author(s)
      茂木立志
    • Journal Title

      J.Biochem. 146

      Pages: 491-499

    • NAID

      10026303861

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of mitochondrial Complex II subunits SDH3 and SDH4 and ATP synthase subunits a and b in Plasmodium spp2009

    • Author(s)
      茂木立志
    • Journal Title

      Mitochondrion 9

      Pages: 443-453

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] ミトコンドリアコハク酸脱水素酵素の退化型サブユニットの発見と集積機構2009

    • Author(s)
      茂木立志
    • Journal Title

      蛋白質核酸酵素 54

      Pages: 1965-1971

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gramicidin S and polymyxins : the revival of cationic cyclic peptide antibiotics2009

    • Author(s)
      茂木立志
    • Journal Title

      Cell.Mol.Life Sciences 66

      Pages: 3821-3826

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of new inhibitors for alternative NADH dehydrogenase (NDH-II)2009

    • Author(s)
      Mogi, T.
    • Journal Title

      FEMS Microbiol. Lett. 291

      Pages: 157-161

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mitochondria dehydrogenases in the aerobic respiratory chain of the rodent malaria parasite Plasmodium yoelii yoelii2009

    • Author(s)
      Kawahara, K., Mogi, T. (6名中2番目)
    • Journal Title

      J. Biochem. 145

      Pages: 229-237

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antibiotics LL-Z1272 identified as novel inhibitors discriminating bacterial and mitochondrial quinol oxidases2009

    • Author(s)
      Mogi, T.
    • Journal Title

      Biochim. Biophys. Acta 1787

      Pages: 129-133

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Characterization of cytochrome bd plasoquinol oxidase from the cyanobacterium Synechocystis sp. PCC 68032009

    • Author(s)
      Mogi, T.
    • Journal Title

      J. Biochem. 145

      Pages: 395-401

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gramicidin S identified as a potent inhibitor for cytochrome bd-type quinol oxidase2008

    • Author(s)
      Mogi, T.
    • Journal Title

      FEBS Lett 582

      Pages: 2299-2302

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glutamate 107 in subunit I of cytochrome bd from Escherichia coli is part of a transmembrane intraprotein pathway conducting protons from the cytoplasm to the heme b595/heme d active site2008

    • Author(s)
      Borisov, V. B., Mogi, T. (5名中4番目)
    • Journal Title

      Biochemistry 47

      Pages: 7907-7914

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Screening of detergents for solubilization, purification and crystallization of membrane proteins: a case study on succinate:ubiquinone oxidoreductase from Escherichia coli2008

    • Author(s)
      Shimizu, H., Mogi, T. (6名中4番目)
    • Journal Title

      Acta Crystallographica F64

      Pages: 858-862

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] Novel mitochondrial Complex II isolated from Trypanosoma cruzi is composed of twelve peptides including a heterodimeric Ip subunit2009

    • Author(s)
      Morales, J., 茂木立志, 4名中2番目
    • Organizer
      日本生体エネルギー研究会第35回討論会
    • Place of Presentation
      旭川医科大学(北海道)
    • Year and Date
      2009-12-18
    • Related Report
      2009 Annual Research Report
  • [Presentation] 酢酸菌呼吸鎖シアン非感受性キノールオキシダーゼ(CIO)の精製と機能解析2009

    • Author(s)
      三浦弘嗣、茂木立志, 7名中5番目
    • Organizer
      日本生体エネルギー研究会第35回討論会
    • Place of Presentation
      旭川医科大学(北海道)
    • Year and Date
      2009-12-18
    • Related Report
      2009 Annual Research Report
  • [Presentation] ユーグレノゾアミトコンドリアの代替的代謝経路と環境適応2009

    • Author(s)
      茂木立志
    • Organizer
      ユーグレナ研究会第25回研究集会
    • Place of Presentation
      大阪府立大学・国際交流会館(大阪府)
    • Year and Date
      2009-11-14
    • Related Report
      2009 Annual Research Report
  • [Presentation] バクテリアの呼吸鎖電子伝達系酵素を標的とする新規阻害剤の同定を目指した天然抗生物質ライブラリーのマトリックススクリーニング2009

    • Author(s)
      茂木立志
    • Organizer
      日本生化学会第82回大会
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2009-10-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] 酢酸菌呼吸鎖末端で機能するシアン非感受性キノールオキシダーゼ(CIO)の精製.2009

    • Author(s)
      三浦弘嗣、茂木立志, 7名中3番目
    • Organizer
      日本生化学会第82回大会
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] Novel mitochondrial Complex II isolated from Trypanosoma cruzi is composed of twelve peptides including a heterodimeric Ip subunit2009

    • Author(s)
      Morales, J., 茂木立志, 4名中2番目
    • Organizer
      日本生化学会第82回大会
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2009-10-22
    • Related Report
      2009 Annual Research Report
  • [Presentation] The respiratory complex II of Trypanosoma cruzi: a novel enzyme from an old parasite2009

    • Author(s)
      Morales, J., Mogi, T. (4名中3番目)
    • Organizer
      日本寄生虫学会第78回大会
    • Place of Presentation
      法政大学市ヶ谷キャンパス
    • Year and Date
      2009-03-27
    • Related Report
      2008 Annual Research Report
  • [Presentation] Diversification of mitochondrial succinate dehydrogenase complex in the Euglenozoa by degeneration of dispersed duplicates2008

    • Author(s)
      Mogi, T.
    • Organizer
      第8回ミトコンドリア学会
    • Place of Presentation
      東京女子医科大学、新宿
    • Year and Date
      2008-12-19
    • Related Report
      2008 Annual Research Report
  • [Presentation] シアノベクテリアSynechocysits sp.PCC6803のシアン耐性シトクロムbdキノ2008

    • Author(s)
      茂木立志
    • Organizer
      日本生化学会第81回大会
    • Place of Presentation
      神戸国艦議揚
    • Year and Date
      2008-12-11
    • Related Report
      2008 Annual Research Report
  • [Presentation] ユーグレナ植物のコハク酸脱水素酵素は新規の超分子呼吸鎖複合体である2008

    • Author(s)
      茂木立志
    • Organizer
      第46回日本生物物理学会
    • Place of Presentation
      福岡国際会議場
    • Year and Date
      2008-12-05
    • Related Report
      2008 Annual Research Report
  • [Presentation] Novel mitochondrial complex II from the parasitic protist Trypanosoma cruzi consists of twelve-subunit with heterodimeric iron-sulfur subunit2008

    • Author(s)
      Kita, K., Mogi, T. (3名中3番目)
    • Organizer
      International Symposium of Protistology: Evolution and Diversity
    • Place of Presentation
      Tsukuba
    • Year and Date
      2008-11-09
    • Related Report
      2008 Annual Research Report
  • [Presentation] ユーグレノゾアにおける分散型重複遺伝子の退化に由来するミトコンドリアのコハク酸脱水素酵素複合体の多様化2008

    • Author(s)
      茂木立志
    • Organizer
      ユーグレナ研究会第24回研究集会
    • Place of Presentation
      近畿大学農学部、奈良
    • Year and Date
      2008-11-09
    • Related Report
      2008 Annual Research Report
  • [Presentation] Analyzing membrane arhors for mitochondria enzymes of malaria parasites2008

    • Author(s)
      Mogi,- T.
    • Organizer
      The 8th Awaj intematinnal Forum on Infecticn and Immimity
    • Place of Presentation
      Awaji, Hyogo
    • Year and Date
      2008-09-10
    • Related Report
      2008 Annual Research Report
  • [Presentation] Divergence in structure of mitochondrial respiratory complex II (succinate-ubiquinone reductase) revealed by protozoan enzymes2008

    • Author(s)
      Morales, J., Mogi, T. ( 9名中2番目)
    • Organizer
      European Bioenergetics Conference 2008
    • Place of Presentation
      Dublin, UK
    • Year and Date
      2008-07-23
    • Related Report
      2008 Annual Research Report
  • [Presentation] Novel subunit organization of the respiratory Complex II (succinate-ubiquinone oxidoreductase) in Trypanosoma cruzi2008

    • Author(s)
      Morales, J., Mogi, T. (3名中2番目)
    • Organizer
      XVIIth International Congress for Tropical Medicine and Malaria
    • Place of Presentation
      Jeju Island, Korea
    • Related Report
      2008 Annual Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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