Structure based study of human serum albumin complex with antibiotics to improve the multidrug antimicrobial therapy.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16060
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Fujita Health University
• Principal Investigator: Kawai Akito 藤田医科大学, 医学部, 講師 (20435150)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 構造生物学 / ヒト血清アルブミン / 薬剤感受性 / 抗菌薬

Outline of Final Research Achievements

Plasma protein binding is an essential factor in drug activity. Some antibiotics interact with human serum albumin (HSA), an abundant protein in human plasma. When the binding fraction was reduced, active drug concentrations are reflected in enhanced antimicrobial activity. However, the knowledge of the detail binding scheme of antibiotics with HSA is limited. In this study, we examined the biding scheme of antibiotics containing typical molecular skeletons to HSA using X-ray crystallography. As a result, we succeed to crystalize seven complexes of HSA and antibiotics and determined four crystal structures. Based on the structure, we selected the competitive drug for binding to HSA and experimentally confirmed that the susceptibility of antibiotics was changed when the competitive drug was present.

Free Research Field

構造生物学

Academic Significance and Societal Importance of the Research Achievements

HSAは抗菌薬だけでなく抗がん剤や抗炎症薬など多くの薬と相互作用し、その結合変化によって薬効が左右される。特に救命的な重要性を有する抗菌薬は静脈内に直接投与されるものが多く、血中HSA濃度と同等になることから、併用薬とHSAの結合部位を取り合えば薬効変化が懸念される。本研究で得られた抗菌薬とHSAの詳細な相互作用様式は、併用注意の薬物リスト作成に役に立ち、効果的な薬物療法の設計に応用されることが期待できる。