Development of novel antibiotics targeting peptidases of non-fermenting gram negative rods.

2019 Fiscal Year Final Research Report

• Project/Area Number: 16H04902
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied microbiology
• Research Institution: Showa University
• Principal Investigator: Tanaka Nobutada 昭和大学, 薬学部, 准教授 (00286866)
• Project Period (FY): 2016-04-01 – 2020-03-31
• 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

Family S46 peptidases are widely distributed in anaerobic Gram-negative species in the genera Bacteroides, Parabacteroides, and Porphyromonas, but they are not found in mammals. Therefore, S46 peptidases are ideal targets for novel antibiotics. We determined a crystal structure of dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) in complex with citrate ions at a 1.50 Å resolution using a high-quality space-grown crystal. The bound citrate ion, a potassium ion, and a water molecule in the active site of PgDPP11 were regarded to mimic the binding of an acidic amino acid and were utilized as a pharmacophore for an in silico inhibitor screening. The screening resulted in the first nonpeptidyl inhibitor of S46 peptidases, SH-5. The binding mode of SH-5 was confirmed by crystal structure analysis at a 2.39 Å resolution. The hit compound SH-5 and a related compound represent promising lead structures for further rational design of potent inhibitors against PgDPP11.

Free Research Field

創薬科学

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。