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二重メカニズムの抗生物質がグラムネガティブの細菌を殺し,薬剤耐性を避ける

James K Martin¹, Joseph P Sheehan¹, Benjamin P Bratton²

¹Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.

|June 5, 2020

まとめ

新しい化合物SCH-79797は 2つの細菌経路を同時に標的にし,抗生物質耐性グラム陰性およびグラム陽性細菌に対する強力な戦略を提供します. イレジスティン16は臨床前モデルで有効性を示した.

科学分野:

微生物学
薬物の発見
抗菌剤に対する耐性

背景:

抗生物質耐性はグラム陰性細菌を標的とした新薬が極めて不足していることで世界的な健康危機を引き起こしています
現存する治療法は,メチチリン耐性黄金球菌 (MRSA) などの耐性菌株に対する効果が低下しています.

研究の目的:

耐性細菌に対する二重標的作用機構 (MoA) を有する新しい化合物SCH-79797の特徴を明らかにする.
難しい細菌感染症の治療のためにより強力な誘導体であるIrresistin-16を開発し評価する.

主な方法:

SCH-79797のMoAを明らかにするために,定量画像,プロテオミクス,遺伝学,メタボロミクス,および細胞ベースのアッセイのパイプラインを使用しました.
SCH-79797およびその誘導体であるIrresistin-16は,MRSAおよびネイスリア・ゴノレアを含む,グラム陰性およびグラム陽性細菌に対して試験された.
イレジスティン16の in vivo 効果を評価するためにマウスの陰道感染モデルを使用した.

主要な成果:

SCH-79797は,葉酸代謝と細菌膜の整合性を標的としたユニークな二重MoAを示しています.
この化合物は検出できないほど低抵抗率を示し,MRSAの持続性に対する組み合わせ治療を上回った.
イレジスティン16は,臨床前のマウスモデルでニセリア・ゴノレアに対する効能と有効性が向上した.

結論:

複数のMOAを単一の分子に結合することは治療が難しい病原菌に対する新しい抗生物質の開発に有望な戦略です
SCH-79797とIrresistin-16は,抗生物質耐性の増大する脅威と戦うための新しい抗菌療法のための有望なリードです.

キーワード:

アシネトバクター・バウマンニグラム陰性病原体ネイセリア・ゴノレア抗生物質幅広いスペクトル二重標的薬物葉酸の代謝膜を壊す

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