A novel approach to drug development targeting to proton pumping ATPase

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06629
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Iwate 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
• Keywords: F-ATPase / A-ATPase / プロトンポンプ / S. anginosus / S. mutans / 虫歯 / 歯周病

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.

Free Research Field

生物化学

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