Development of novel antimicrobial drugs targeting pathogen effectors

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K15750
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38030:Applied biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Nishide Akira 京都大学, 医学研究科, 特定研究員 (80807652)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ユビキチン / エフェクター / 病原細菌 / 抗菌薬

Outline of Final Research Achievements

Pathogens secrete protein X, are ubiquitin ligase into host cells during infection. Protein X induce host proteins to proteasomal degradation and disrupt host cell immune response. The goal is discover protein X inhibitor as the novel antimicrobial drugs by evaluating the inhibition activity of candidates that bind to protein X.
As the results of in vitro inhibition assay, we confirmed protein X inhibition in two compounds of more than 200 candidates. Furthermore, we observed that one of two compounds inhibited protein X by measuring the inhibition activities in culture cells. In addition, we establish compound quantitative evaluating method with using that cells. Identified compound is required further evaluation and optimization, but has potential to become a new antimicrobial drug.

Free Research Field

応用生物化学

Academic Significance and Societal Importance of the Research Achievements

近年、続々と出現する耐性菌は抗菌薬に耐性をもち、さらに類似の構造や作用機構の抗菌薬に対しても耐性を持つ。その一方で、既存の抗菌薬の作用機構は大きくわけて４種のみで遠くない未来、あらゆる抗菌薬の効かない耐性菌の出現が危ぶまれている。こういった背景から、新規の作用機構を持つ抗菌薬の開発が強く求められている。
本研究の結果、候補化合物の中から細胞内外で標的であるタンパク質Ｘのユビキチンリガーゼ活性を阻害する化合物を見出した。病原性細菌が分泌するタンパク質を標的にした薬剤はこれまでに存在せず、今後、見出した化合物についてさらなる評価・最適化を行うことで、新規抗菌薬となることが期待される。