グラム陰性細菌に対するキメリックペプチドミメティック抗生物質
Anatol Luther1, Matthias Urfer2, Michael Zahn3
1Polyphor AG, Allschwil, Switzerland.
Nature
|October 25, 2019
まとめ
新しい合成抗生物質は 危険なグラム陰性病原体に対抗し 現在の薬剤に耐性があります これらの新しい化合物は 細菌の膜を標的とし 多剤耐性感染症と コリスチン耐性を克服する 可能性を示しています
科学分野:
- 薬剤化学
- 微生物学
- 薬物の発見
背景:
- カーバペネムと第3世代のセファロスポリンに耐性を持つ グラム陰性病原体に対する新しい抗生物質の緊急需要
- 最終手段の抗生物質は これらの多剤耐性 (MDR) 病原体に対して 効力を失っています
- ESKAPEの病原体は,抗菌剤耐性による世界的な健康上の重大な脅威です.
研究 の 目的:
- カーバペネム耐性グラム陰性細菌を標的とした 新種の合成抗生物質を開発する
- これらの新しいキメリック抗生物質の作用メカニズムを調査する.
- MDR病原体に対する最適化派生体の有効性と薬剤特性を評価する.
主な方法:
- β-ヘアピンペプチドマクロサイクルとポリミキシン/コレスティンの天然製品構造を組み合わせたキメリック抗生物質の設計と合成.
- リポポリサッカリド (LPS) とβ-バーレルの外膜タンパク質Bammaへの結合を含む,細菌滅菌活性と作用機構の評価
- ESKAPE病原体を含む多剤耐性グラム陰性病原体に対する最適化された誘導体のin vitroおよびin vivo評価.
- コリスチン耐性および薬物の性質の評価
主要な成果:
- グラム陰性病原体に対する強力な殺菌活性を持つ合成キメリック抗生物質を開発した.
- LPS結合とβ-バレルの折り畳み複合体におけるBamaタンパク質の阻害を含む二重の作用メカニズムが示された.
- ESKAPE病原体を含む様々なMDRグラム陰性細菌に対する高効性を示した.
- 既存のコリスチン耐性メカニズムを in vitro と in vivo で克服し,薬剤に好ましい性質を示した.
結論:
- この新種の合成抗生物質は,MDRのグラム陰性病原体による生命を脅かす感染症の治療に 重要な可能性を秘めている.
- 作用の双重メカニズムと抵抗を克服する能力により,これらの化合物は,満たされていない重要な医学的ニーズに対処するための有望な候補となります.
- 主要候補は臨床前毒学研究に進み 臨床試験への道を切り開いています
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