Biosynthetic studies of aromatic polyketides to overcome tetracyclin-resistance of Escherichia coli.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08350
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Natural medicines
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Taguchi Takaaki 国立医薬品食品衛生研究所, 食品部, 室長 (80409383)
• Co-Investigator(Kenkyū-buntansha): 市瀬 浩志 武蔵野大学, 薬学部, 教授 (40282610)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: アクチノロジン / 生合成 / 酸素添加 / 水酸化 / エノイル還元 / テトラサイクリン耐性率

Outline of Final Research Achievements

Actinorhodin (ACT) and tetracyclines belong to a class of aromatic polyketide antibiotics. To produce new derivatives of ACT efficiently by biosynthetic engineering, in vitro reconstitution of their biosynthesis is very important. The two-component flavin-dependent monooxygenase system and enoyl reductase involved in ACT biosynthesis were heterologously expressed. In vitro assay conditions were successfully optimized, allowing for a clear understanding of enzymatic mechanisms and substrate specificities. Furthermore, the combination of the monooxygenase system and the enoyl reductase revealed new problems to be solved. In vitro reconstitution of ACT biosynthesis will soon be achieved based on the results of this study, and substances that decrease tetracycline-resistance rates will thus be identified.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

大腸菌のテトラサイクリン耐性率低下は世界的に喫緊な課題の一つであり、大腸菌の薬剤排出ポンプの阻害剤を新規に創出できれば、この課題解決に寄与できる。本研究により、テトラサイクリンと類似している抗生物質アクチノロジンの、生合成に関わる酵素の一部について発現系、反応系を構築でき、反応機構を明らかとしたことの学術的な意義は大きい。加えて、生合成全体の試験管での再構成と新規阻害剤の創出の可能性も高まり、耐性率低下という社会的な課題解決の一助となる。