ノボビオシンは,リポポリサカリド輸送を刺激することによってポリミキシンの活性を増強する

Michael D Mandler¹, Vadim Baidin¹, James Lee¹

¹Department of Chemistry and Chemical Biology , Harvard University , Cambridge , Massachusetts 02138 , United States.

Journal of the American Chemical Society

|May 11, 2018

まとめ

リポポリサッカリド (LPS) 輸送強化ポリミキシンを標的とするノボビオシンの誘導体

科学分野:

微生物学
薬物の発見
生物化学

背景:

抗生物質の有効性を阻害する難しい外膜を持っています
コリスチンのようなポリミキシンは最後の抗生物質ですが毒性があります
ノボビオシンはポリミキシンと作用し,外膜への浸透を助長する.

研究の目的:

異なる活動を持つノボビオシン誘導体を合成し評価する.
ポリミキシンとノボビオシンのシナジーにおけるLptB刺激の役割を調査する.
グラム陰性感染症の改善された併用療法を開発する.

主な方法:

新種のノボビオシンアナログの合成
DNAギラゼ阻害とLptB刺激を分離する.
ポリミキシンとの相乗効果による致死性の評価

主要な成果:

LptBを刺激するノボビオシンアナログはDNAギラゼを抑制せず,ポリミキシンの致死性を高めました.
これは,リポポリサッカリド (LPS) 輸送アゴニズムがシナジーに有意に寄与することを示しています.
LptB結合が強化された他の類剤は,ポリミキシンでより高い効能を示した.

結論:

LPSの輸送を刺激することは,ノボビオシン-ポリミキシンのシナジーにとって重要なメカニズムです.
最適化されたノボビオシン類は,ポリミキシンの有効性と安全性を改善することができます.
LPS輸送をターゲットにするとグラム陰性細菌に対する有望な戦略になります

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