Building a molecular basis for multidrug efflux pump inhibitors effective against multidrug-resistant Pseudomonas aeruginosa infections

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07547
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49050:Bacteriology-related
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Morita Yuji 明治薬科大学, 薬学部, 教授 (00454322)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 多剤耐性緑膿菌 / 多剤排出ポンプ / アミノグリコシド / ベルベリン

Outline of Final Research Achievements

Amino acid residues of MexY that presumed to bind to the aminoglycoside are predicted from its estimated three-dimensional structure. The results of the drug susceptibility test suggested some amino acid residues of MexY contributes to the aminoglycoside resistance. Furthermore, we found that MexXY expression decreased production of pyoverdine in Pseudomonas aeruginosa. Pyoverdine is a siderophore and a virulence factor for Pseudomonas aeruginosa. When MexY molecular docking was performed with reference to the AcrB crystal structure of Escherichia coli etc., both amikacin and berberine (derivative) bound to the estimated proximal binding site of MexY, and competitive inhibition of both inhibited amikacin resistance by MexY. This result was consistent with the MexY mutation sites that reduced aminoglycoside resistance and inhibition of berberine (derivative).

Free Research Field

微生物学

Academic Significance and Societal Importance of the Research Achievements

多剤耐性緑膿菌感染症の治療に有効な抗菌薬はほとんどない。一方で、緑膿菌は多くの抗菌性化合物に自然耐性を示すため、新規抗緑膿菌薬の開発は容易でない。研究代表者が発見したベルベリンは緑膿菌の多剤排出系MexXYを阻害してアミノグリコシドなどの耐性を軽減する。今回の研究でMexXYに対するアミノグリコシドやベルベリンの作用の分子機構の一端を示すことができた。多剤耐性緑膿菌感染症の治療に使用できなくなった抗菌薬を復活させる阻害剤の分子機構の解明は、阻害剤をリード化合物とした創薬に有用な情報を提供する。