Comprehensive structure-activity relationship analysis with substrates for the development of inhibitors of multidrug efflux complexes.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K19337
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 47:Pharmaceutical sciences and related fields
• Research Institution: Osaka University
• Principal Investigator: Yamashita Eiki 大阪大学, 蛋白質研究所, 准教授 (00294132)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Keywords: 構造生物 / 相互作用解析 / 薬剤排出タンパク質複合体

Outline of Final Research Achievements

The multidrug resistance of Gram-negative bacteria is closely related to the RND-type multidrug efflux complexes, which recognize and efflux a variety of antimicrobial agents from the bacteria. In this study, to accumulate structure-activity relationship information for the development of inhibitors targeting RND-type multidrug efflux complexes, we conducted interaction analysis and X-ray crystallographic analysis to examine the detailed interaction between the transporter MexB of the RND-type multidrug efflux complex MexAB-OprM expressed in Pseudomonas aeruginosa and its substrates, and established the fundamental conditions necessary for a comprehensive analysis.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

グラム陰性菌の多剤耐性に関わる排出タンパク質複合体の機能を阻害する分子が開発されれば、治療効果が弱まったが承認されている抗菌剤が再び治療に活用でき、また、投薬量を減らすことができる可能性がある。これにより、抗菌薬の過剰投与による環境汚染や新たな耐性菌の発生リスクも抑えられる。本研究で確立した方法を用いれば、多剤排出タンパク質複合体の相関構造解析を効率的に進め、多剤耐性菌の問題解決に繋がると考えている。