Development of drug leads for drug-resistance bacterial pathogens based on natural products

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05097
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Hokkaido University
• Principal Investigator: Satoshi Ichikawa 北海道大学, 薬学研究院, 教授 (60333621)
• Research Collaborator: Katsuyama Akira ; Sato Toyotaka ; Lee Seok-Yong
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 薬剤耐性菌 / 天然物 / 創薬化学 / 有機合成化学

Outline of Final Research Achievements

1)Synthesis and biological evaluation of muraimycin analogues were investigated. 2) Synthesis of the core structure of phaerimycin and its derivatives was achieved and their MraY inhibitory activity was also conducted. As a result, one derivative showed high MraY inhibitory activity. 3) Mureidomycin A analigues were synthesized and it was found that some derivatives exhibited higher MraY inhibitory activity and anti-P. aeruginosa activity than pacidamycin D, which is a conger of mureidomycin A. Furthermore, X-ray crystal structure analysis of the complex of mureidomycin analogue bound to MraY was also established. 4) The synthesis and action mechanism analysis of plasbacin A3 and its derivative were conducted. 5) In order to find an effective derivative against colistin resistant bacteria, 30 colistin derivatives were synthesized and their antibacterial activities were evaluated.
Some drug resistant bacterial drug lead were developed in this study.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

薬剤耐性菌に対する新規薬剤の開発は世界的急務である。本申請研究は、グラム陽性菌・グラム陰性菌双方の新規多剤耐性抗菌薬のシード供給を実現すべく、複数の天然物を研究対象として誘導体合成の効率的な供給と理論的薬物設計を通して、活性増強・毒性の低減・低分子化等をはかり、効率的にシードを獲得する。創薬ターゲットは従来の薬剤にはない新規作用機序を原則とし、ヌクレオシド系天然物とペプチド系天然物をベースとして、それぞれにグラム陽性菌・グラム陰性菌に対抗できる天然物を研究対象とする。抗薬剤耐性菌薬リードを開発する本研究の成果は、将来的に世界的な健康福祉の維持、QOLの向上に大きく貢献する事が予想される。