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A novel approach to drug development targeting to proton pumping ATPase

Research Project

Project/Area Number 18K06629
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionIwate Medical University

Principal Investigator

Sekiya Mizuki  岩手医科大学, 薬学部, 助教 (70509033)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
KeywordsF-ATPase / A-ATPase / プロトンポンプ / S. anginosus / S. mutans / 虫歯 / 歯周病 / プロトン輸送ATPase / ポリフェノール / ATP synthase
Outline of Final Research Achievements

We focused on proton-pumping ATPase as a target for novel anti-bacterial agents since the enzymes are essential for bacterial growth and survival and are composed of various subunits with many pharmacophores.
We studied the effects of inhibitors of proton-pumping F-ATPase on the growth and survival of oral pathogenic bacteria, S. mutans and S. anginosus under acidic conditions. F-ATPase inhibitors decreased the growth of these bacteria pH5.3. They also significantly reduced the colony-forming ability of them after incubation at pH 4.3, while showing less effect at pH 7.3. These observations indicate that S. mutans and S. anginosus are highly sensitive to F-ATPase inhibitors under acidic conditions. F-ATPase deficient S. anginosus exhibited essentially the same phenotype as that of wild-type with F-ATPase inhibitors, suggesting that F-ATPase plays an important role in acid tolerance of these bacteria.

Academic Significance and Societal Importance of the Research Achievements

本研究課題の成果により、口腔内病原細菌であるS. mutans、S. anginosusの耐酸性にプロトン輸送ATPaseが重要であることが示唆された。また、複数のポリフェノール化合物が同酵素を阻害し、これらの細菌の耐酸性を低下させることを明らかにした。プロトン輸送ATPaseは多数のサブユニットから構成される巨大分子であり、作用点の異なる阻害化合物を組み合わせることでよりより強力な抗菌作用が期待できる。また、ポリフェノール類は食品にも含まれるため、安全性が高い。本研究成果は、新たなう蝕・歯周病の予防薬、または口腔ケア用品の開発につながると考えられる

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (19 results)

All 2021 2020 2019 2018

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (14 results) (of which Int'l Joint Research: 2 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Functional complementation of V-ATPase a subunit isoforms in osteoclasts2020

    • Author(s)
      Matsumoto Naomi、Sekiya Mizuki、Fujimoto Yasuyuki、Haga Satoshi、Sun-Wada Ge-Hong、Wada Yoh、Nakanishi-Matsui Mayumi
    • Journal Title

      The Journal of Biochemistry

      Volume: - Issue: 4 Pages: 459-466

    • DOI

      10.1093/jb/mvaa118

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase2019

    • Author(s)
      YasumitsuSakamoto,YoshiyukiSuzuki,AkihiroNakamura,YurieWatanabe,MizukiSekiya,SaoriRoppongi,ChisatoKushibiki,IppeiIizuka,OsamuTani,HitoshiSakashita,KojiInaka,HiroakiTanaka,MitsuguYamada,KazunoriOhta,NobuyukiHonma,YosukeShida,WataruOgasawara,MayumiNakanishi-Matsui,TakamasaNonaka,HiroakiGouda & NobutadaTanaka
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 13587-13587

    • DOI

      10.1038/s41598-019-49984-3

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Proton-pumping F-ATPase plays an important role in Streptococcus mutans under acidic conditions2019

    • Author(s)
      Sekiya Mizuki、Izumisawa Shintaro、Iwamoto-Kihara Atsuko、Fan Yang、Shimoyama Yu、Sasaki Minoru、Nakanishi-Matsui Mayumi
    • Journal Title

      Archives of Biochemistry and Biophysics

      Volume: 666 Pages: 46-51

    • DOI

      10.1016/j.abb.2019.03.014

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Essential Role of the a3 Isoform of V-ATPase in Secretory Lysosome Trafficking via Rab7 Recruitment2018

    • Author(s)
      Matsumoto N, Sekiya M, Tohyama K, Ishiyama-Matsuura E, Sun-Wada GH, Wada Y, Futai M, Nakanishi-Matsui M.
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 6701-6701

    • DOI

      10.1038/s41598-018-24918-7

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 多剤耐性菌Stenotrophomonas maltophiliaに抗菌活性を示すジペプチド 誘導体の開発2021

    • Author(s)
      日高興士、橋本大聖、関拓海、櫻井有紀、阪本泰光、六本木沙織、關谷瑞樹、中村彰宏、鈴木義之、小笠原渉、田中信忠、宮崎杏奈、北條恵子、津田裕子
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] インスリン分泌小胞の輸送における V-ATPase a2 イソフォームの機能2020

    • Author(s)
      關谷瑞樹、松元奈緒美、矢野志緒、河野喜久子、中西(松井)真弓
    • Organizer
      第93回日本生化学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Development of Antimicrobial Dipeptides Targeting Dipeptidyl Peptidase 7 of Stenotrophomonas maltophilia2020

    • Author(s)
      Hidaka, K., Hashimoto, T., Seki, T., Sakurai, Y., Sakamoto, Y., Roppongi, S., Sekiya, M., Nakamura, A., Ogasawara, W., Suzuki, Y., Tanaka, N., Miyazaki, A., Hojo, H. and Tsuda, Y.
    • Organizer
      第57回ペプチド討論会
    • Related Report
      2020 Annual Research Report
  • [Presentation] アンギノーサスレンサ球菌の酸性環境におけるプロトン輸送ATPaseの役割2020

    • Author(s)
      関谷瑞樹、村上幸汰、高坂未星、松元奈緒美、下山佑、石河太知、河野喜久子、矢野志緒、佐々木実、中西(松井)真弓
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
  • [Presentation] V-ATPase a3 isiform is involved in trafficking of osteoclast secretory lysosomes2019

    • Author(s)
      Mayumi Nakanishi-Matsui, Naomi Matsumoto, Mizuki Sekiya, Ge-Hong Sun-Wada, Yoh Wada, Koujiro Tohyama, Eri Ishiyama-Matsuura, Masamitsu Futai
    • Organizer
      27th FAOBMB Conference in Kuala Lumpur
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] Streptococcus anginosus の酸性環境におけるプロトン輸送ATPaseの役割2019

    • Author(s)
      關谷瑞樹、高坂未星、矢野志緒、河野喜久子、佐々木実、中西(松井)真弓
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] V-ATPase a3 アイソフォームが関与する分泌リソソームの細胞内輸送機構2019

    • Author(s)
      松元奈緒美、關谷瑞樹、遠山稿二郎、石山(松浦)絵里、和田(孫)戈虹、和田洋、二井將光、中西(松井)真弓
    • Organizer
      第92回日本生化学会大会
    • Related Report
      2019 Research-status Report
  • [Presentation] 細菌DPP7を標的とするジペプチド型阻害剤のSBDDとエステル誘導体の開発2019

    • Author(s)
      日高興士、橋本大聖、関拓海、櫻井有紀、中村彰宏、鈴木義之、小笠原渉、六本木沙織、阪本泰光、關谷瑞樹、田中信忠、北條恵子、津田裕子
    • Organizer
      第37回メディシナルケミストリーシンポジウム
    • Related Report
      2019 Research-status Report
  • [Presentation] 口腔レンサ球菌の酸性環境におけるプロトン輸送 ATPase の役割2019

    • Author(s)
      関谷瑞樹、高坂未星、伊藤槻、櫻直也、 泉澤信太郎、楊帆、岩本(木原)昌子、石河太知、下山佑、 佐々木実、中西(松井)真弓
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] プロトン輸送 ATPase 阻害剤は歯周病菌 P. gingivalis の増殖を阻害する2018

    • Author(s)
      關谷瑞樹、下山佑、石河太知、高橋歩実、小田原大樹、佐々木実、二井將光、中西(松井)真弓
    • Organizer
      第84回日本生化学会東北支部例会・シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] V-ATPase a3アイソフォームのリソソーム輸送における機能2018

    • Author(s)
      松元奈緒美、關谷瑞樹、遠山稿二郎、石山(松浦)絵里、和田(孫)戈虹、和田洋、二井將光、中西(松井)真弓
    • Organizer
      第84回日本生化学会東北支部例会・シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] Essential role of proton pumping F-ATPase in acid tolerance of Streptococcus mutans2018

    • Author(s)
      Sekiya Mizuki, Izumisawa Shintaro, Kushigeta Aki, Haga Masato, Shimoyama Yu, Sasaki Minoru, Kimura Shigenobu, Sasaki Yuka, Iwamoto-Kihara Atsuko, Nakanishi-Matsui Mayumi
    • Organizer
      IUBMB SEOUL
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] プロトン輸送 F-ATPase 阻害剤によるStreptococcus mutans の耐酸性の低下2018

    • Author(s)
      關谷瑞樹、泉澤信太郎、櫛桁安生、芳賀雅人、下山佑、石河太知、佐々木実、佐々木由香、岩本(木原)昌子、中西(松井)真弓
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] V-ATPase a3アイソフォームは破骨細胞の分泌リソソームの細胞内輸送に必須である2018

    • Author(s)
      松元奈緒美、関谷瑞樹、遠山稿二郎、石山(松浦)絵里、和田(孫)戈虹、和田洋、二井將光、中西(松井)真弓
    • Organizer
      第41回日本分子生物学会年会
    • Related Report
      2018 Research-status Report
  • [Patent(Industrial Property Rights)] ペプチド型細菌ジペプチジルペプチダーゼ7阻害剤2018

    • Inventor(s)
      日高興士、津田裕子、阪本泰光、關谷瑞樹、小笠原渉
    • Industrial Property Rights Holder
      日高興士、津田裕子、阪本泰光、關谷瑞樹、小笠原渉
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Acquisition Date
      2018
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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