リボソーム 結合 の ため に 準備 さ れ た 抗生物質 が 抗菌 剤 耐性 を 克服 する
Kelvin J Y Wu1, Ben I C Tresco1, Antonio Ramkissoon1
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
まとめ
新しい抗生物質であるクレソマイシン (CRM) は,薬剤耐性菌と効果的に戦う. 細菌のリボソームに結合し,抗菌酵素によって改変されても抗菌剤耐性に対する潜在的な解決策となる.
科学分野:
- 薬剤化学
- 微生物学
- 構造生物学
背景:
- 現代の抗生物質は 進化する多剤耐性細菌に対して ますます無効になっています
- 新種の抗菌剤は 抗菌剤耐性の増大する脅威に対処するために 緊急に必要とされています
- 既存の抗生物質は,細菌がリボソームのRNA改変のような耐性メカニズムを開発すると失敗します.
研究 の 目的:
- クレソマイシン (CRM) の設計,合成,評価について報告する.
- 多剤耐性菌株を含む幅広い細菌に対するCRMの有効性を調査する.
- CRMの作用メカニズムと抵抗を克服する能力の構造的基礎を明らかにする.
主な方法:
- クレソマイシン (CRM) の化学合成と微生物学的評価
- 密度関数理論の計算とX線結晶学 (溶液状態,固体状態,リボソーム結合) を用いてCRMの構造の決定.
- 野生型および改変された細菌のリボソーム (CfrおよびErmメチラゼ) のCRMリボソーム複合体の分析.
主要な成果:
- クレソミシン (CRM) は,グラム陽性およびグラム陰性細菌に対する in vitroおよびin vivoの有効性を示しており,耐性菌株であるStaphylococcus aureus,Escherichia coli,Pseudomonas aeruginosaを含む.
- 構造的研究により,CRMはリボソーム結合に高度に前編成され,異なる状態で同一のマクロサイクルサブユニット配列があることが明らかになった.
- X線結晶学では,CRMがCfrとErmメチラゼによって改変されたリボソームに結合し,抵抗メカニズムに順調に適応することを示しています.
結論:
- クレソマイシン (CRM) は,様々な抗菌剤耐性メカニズムを克服できる有望な新種の抗生物質を表しています.
- 前もって組織された構造と 適応可能な結合モードにより 他の抗生物質が失敗する 細菌のリボソームを 効果的に標的とすることができるのです
- この研究は,耐性感染症と戦うための次世代の抗生物質の開発のための構造的基盤を提供します.
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