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合成のA群の抗生物質で,Vat耐性を克服する
Qi Li1, Jenna Pellegrino2, D John Lee2
1Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
Nature
|September 24, 2020
まとめ
研究者は細菌の耐性に対抗するために 新種のグループAの estreptogramin抗生物質を設計しました これらの新しい化合物は,耐性のある黄色のステーキ菌に対して有望であり,既存の抗生物質のクラスを活性化することができます.
科学分野:
- 微生物学
- 薬物の発見
- 構造生物学
背景:
- 抗生物質の重要な源は 自然産物ですが 耐性メカニズムは共進化しています
- バージニアマイシンアセチルトランスフェラーゼ (Vat) 酵素は,強力な抗生物質であるストレプトグラムリンに耐性を与える.
- 複雑なストレプトグラムリン構造を改変して Vat抵抗を克服することは困難でした.
研究 の 目的:
- 構造的変異性を持つ新型のグループAのストレプトグラムリン類素を設計し合成する.
- 耐性菌株に対するこれらの類似体の抗菌活性を評価する.
- 細菌のリボソームとの結合相互作用を理解する.
主な方法:
- 合理的な設計とストレプトグラムリン類のモジュール化化学合成
- 高解像度冷凍電子顕微鏡と力場ベースの精製
- in vitro アセチル化試験と in vivo マウス感染モデル
主要な成果:
- 構造的に異なった8つの類似体が合成され評価された.
- ペプチジル tRNA結合部位と新生ペプチドの脱出トンネルを含む,リボソーム内の結合相互作用が示されました.
- アナログの1つは,ストレプトグラムリン耐性黄金球菌に対する強力な活性を示し,アセチル化が低下し,マウス感染モデルでの有効性を示した.
結論:
- 合理的な設計と合成により 抗生物質の自然抵抗を克服できます
- Vat媒介による耐性に対抗するために,新しいストレプトグラミン類が開発される.
- このアプローチは,耐性問題に直面している抗生物質のクラスを活性化するための戦略を提供します.
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