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II型脂肪酸合成は,グラム陽性病原体に対する適切な抗生物質標的ではありません

Sophie Brinster¹, Gilles Lamberet, Bart Staels

¹Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.

|March 6, 2009

まとめ

脂肪酸合成II (FASII) 経路を標的とした抗生物質の開発は欠陥があります. ヒトの血清にあるような外来脂肪酸は,バクテリアがFASII阻害を回避することを可能にし,これらの薬はグラム陽性感染症に対して無効になります.

科学分野:

微生物学微生物学とは
ドラッグ・ディスカバリー・ドリッグ・ディスカバリー・ドリッグ・ディスカバリー・ドリッグ・ディスカバリー
バイオケミストリーバイオケミストリー

背景:

タイプII脂肪酸合成 (FASII) 経路は,細菌の生存に不可欠と考えられています.
FASIIを標的とする抗菌薬は,多耐性グラム陽性細菌に対して有望であることが示されています.

研究の目的:

抗生物質開発のためのFASII経路をターゲットにすることの根本的な有効性を調査する.
外来脂肪酸が,グラム陽性病原体におけるFASII経路阻害を克服できるかどうかを判断する.

主な方法:

グラム陽性細菌の病原体 (ストレプトコック,エンテロコック,スタフィロコック) を用いたインビトロおよびインビボ実験.
細菌の成長とFASII遺伝子発現の評価,外部脂肪酸とヒト血清の存在下.
Streptococcus agalactiae.におけるFASII標的遺伝子削除変異体の生成と分析

主要な成果:

ヒトの血清に容易に含まれている外来脂肪酸は,抗菌薬によるFASII経路阻害を効果的に回避します.
主要なグラム陽性病原菌は,外来脂肪酸を供給すると,薬物誘発のFASII阻害を克服する.
FASII経路酵素は,Streptococcus agalactiaeの感染中に,遺伝子削除であっても,体内では欠かせないことが判明しました.

結論:

FASII経路を標的とする抗生物質の開発戦略は,バイパスメカニズムのために根本的に欠陥があります.
人間の血清は脂肪酸の重要な源として作用し,FASII標的薬の有効性を損なう.
FASIIベースの抗菌剤は,グラム陽性病原体によって引き起こされるセプシスの治療に効果的ではない可能性があります.

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