単純な二次アミンは,フェニララニル-tRNA合成酵素に高度に選択的に結合することによって,グラム陰性細菌の成長を抑制する
Vadim Baidin1, Tristan W Owens1, Michael B Lazarus2
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Journal of the American Chemical Society
|January 7, 2021
まとめ
新しい二次アミン抗生物質は,PheRS酵素を阻害することで,選択的にグラム陰性細菌を標的とする. この発見は 薬剤耐性グラム陰性感染症に対する 新しい治療法の開発に 有望な基盤を提供します
科学分野:
- 薬剤化学
- 微生物学
- 構造生物学
背景:
- 薬剤耐性グラム陰性感染症は,世界的な健康上の重大な脅威となり,新たな抗生物質の発見が求められます.
- 既存の治療法は限られており,これらの病原体に対する新しい抗菌剤の開発は困難です.
研究 の 目的:
- 薬剤耐性グラム陰性細菌に対する活性を持つ新しい化合物を特定し,特徴づけること.
- 新たに特定された抗生物質の作用と選択性の解明
主な方法:
- 細胞ベースのスクリーンは,グラム陰性細菌の成長阻害剤を特定するために使用されました.
- 耐性変異は標的酵素を特定するためにマッピングされ,その後に生化学的測定が行われました.
- 阻害剤と複合した標的酵素の結晶構造を決定した.
- 選択性を理解するために,バイオ情報分析と変異生成が使用されました.
主要な成果:
- 単純な二次アミンは, *Escherichia coli* と *Acinetobacter baumannii* の増殖を抑制するが, *Bacillus subtilis* の増殖を抑制しないことが判明した.
- 耐性変異はアミノアシル-tRNA合成酵素 PheRS にマッピングされ,標的として確認されました.
- 構造的および生化学的研究により,この化合物は特定の疎水性ポケットを誘導することによって,選択的にグラム陰性PheRSを抑制することが明らかになった.
- この化合物は,野生型のグラム陰性病原体に対する活性を示し,哺乳類の細胞に毒性はありませんでした.
結論:
- 新しい二次アミン基板は,グラム陰性PheRSを選択的に標的にし,新しい抗生物質の開発に有望な出発点を提供します.
- 化合物の選択性は,グラム陰性PheRSに独特の水性ポケットを誘導する能力に基づいています.
- 抗生物質を併用して 難しいグラム陰性感染症を 治療する可能性を秘めています
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