Development of a novel inhibitor cocktail targeting peptidases from sugar non-fermentative bacteria

2022 Fiscal Year Final Research Report

• Project/Area Number: 19H02876
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 38020:Applied microbiology-related
• Research Institution: Kitasato University (2020-2022); Showa University (2019)
• Principal Investigator: Tanaka Nobutada 北里大学, 薬学部, 教授 (00286866)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: 糖非発酵性細菌 / ペプチダーゼ / 立体構造 / 抗菌剤 / ドラッグデザイン

Outline of Final Research Achievements

Peptidases belonging to the S46 family are absent in humans and are ideal targets for novel antibiotics. In the case of dipeptidyl peptidase 11 (PgDPP11) from the periodontopathogen Porphyromonas gingivalis, we found a completely novel skeleton of PgDPP11 inhibitor based on a pharmacophore model of the binding mode of SH-5, a nonpeptidic PgDPP11 inhibitor found in our previous studies. For DPP7 from the multidrug-resistant Stenotrophomonas maltophilia, we elucidated the molecular mechanism of substrate preference at the S2 subsite by biochemical analyses and high-resolution crystal structure analyses of the complex with four kinds of dipeptides. SmDPP7 prefers more bulky amino acids as P2 residues, but exceptionally, it can successfully recognize asparagine side chains by a hydrogen bond network.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

歯周病原因菌Porphyromonas gingivalisや多剤耐性菌Stenotrophomonas maltophiliaは糖ではなく蛋白質やペプチドをエネルギー源とする「糖非発酵性細菌」である。従って、これらの菌のペプチド代謝経路を阻害するような化合物は新規抗生物質と成り得る。従って、本研究の学術的意義は、糖非発酵性細菌を標的とした新規抗生物質開発に繋がるものである。また、本研究の社会的意義として、製薬企業は感染症関連研究に対して消極的なため大学研究者による抗生物質開発に繋がる基盤研究は社会的に極めて重要であることを強調したい。