マクサミシンの異なる総合成と特徴付け
Journal of the American Chemical Society
|June 6, 2023
まとめ
マクサミシンと呼ばれるヴァンコマイシン類の新合成は,耐性細菌に対して有効な強力な抗菌剤を提供します. これらの新薬はMRSAやVRSAのような 挑戦的な菌株に対して in vivoで有効性を示しています
科学分野:
- 薬剤化学
- 有機合成
- 抗菌薬の発見
背景:
- バンコミシンは 重要な抗生物質ですが 耐性菌は 増大する脅威です
- 新型バンコミシンアナログの開発は,耐性グラム陽性感染症との闘いにおいて極めて重要です.
- ヴァンコマイシン類の合成経路は,しばしば長続きし,低収量である.
研究 の 目的:
- ポケット改造バンコマイシン アナログの簡潔でスケーラブルな合成を開発する.
- ヴァンコマイシン アナログの様々な改変のための共通の中間物質を作成する.
- 強化された抗菌特性を持つ新しいマキシミシンを合成し,評価する.
主な方法:
- 共通の末期中間物質である [Ψ[C(S) NH]Tpg4]バンコミシンを生成する分散した全合成アプローチ.
- アグリコンのアトロポセレクティブ合成とワンポット酵素グリコシル化.
- チオアミドからアミジン/アミノメチレンへの後期的な変換と,周辺の改変の組み込み
主要な成果:
- 重要な中間物質のスケーラブルな合成 (18段階,12%の収量,>5g) により,さまざまな類型にアクセスできます.
- 強力で耐久的で有効な抗菌作用を持つ新しいアミジンベースのマキシミシンを成功裏に合成した.
- バンコミシンに敏感で耐性のあるグラム陽性生物に対して同効性があり,3つの作用機構がある.
結論:
- 開発された合成戦略は,新しいバンコミシンとマクサミシンアナログへの広範なアクセスを提供します.
- 新しいアミジンベースのマクサミシンは 次世代の抗生物質として大きな可能性を秘めている.
- 1つのマクサミシンアナログ (MX- 4) は,挑戦的なMRSAおよびVRSA株に対するインビオ有効性を示した.
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