Ruhr-Universität Bochum, Mikrobielle Antibiotikaforschung, Biologie der Mikroorganismen, Universitätsstraße 150, Bochum 44801, Germany.
Antimicrob Agents Chemother. 2011 Jun;55(6):2590-6. doi: 10.1128/AAC.00078-11. Epub 2011 Mar 7.
Fatty acid biosynthesis is a promising novel antibiotic target. Two inhibitors of fatty acid biosynthesis, platencin and platensimycin, were recently discovered and their molecular targets identified. Numerous structure-activity relationship studies for both platencin and platensimycin are currently being undertaken. We established a proteomic signature for fatty acid biosynthesis inhibition in Bacillus subtilis using platencin, platensimycin, cerulenin, and triclosan. The induced proteins, FabHA, FabHB, FabF, FabI, PlsX, and PanB, are enzymes involved in fatty acid biosynthesis and thus linked directly to the target pathway. The proteomic signature can now be used to assess the in vivo mechanisms of action of compounds derived from structure-activity relationship programs, as demonstrated for the platensimycin-inspired chromium bioorganometallic PM47. It will further serve as a reference signature for structurally novel natural and synthetic antimicrobial compounds with unknown mechanisms of action. In summary, we described a proteomic signature in B. subtilis consisting of six upregulated proteins that is diagnostic of fatty acid biosynthesis inhibition and thus can be applied to advance antibacterial drug discovery programs.
脂肪酸生物合成是一个很有前途的新型抗生素靶标。最近发现了两种脂肪酸生物合成抑制剂，platencin 和 platensimycin，并确定了它们的分子靶标。目前正在对 platencin 和 platensimycin 进行大量的结构-活性关系研究。我们使用 platencin、platensimycin、cerulenin 和三氯生在枯草芽孢杆菌中建立了脂肪酸生物合成抑制的蛋白质组学特征。诱导的蛋白 FabHA、FabHB、FabF、FabI、PlsX 和 PanB 是参与脂肪酸生物合成的酶，因此直接与靶途径相关。该蛋白质组学特征现在可用于评估源自结构-活性关系计划的化合物的体内作用机制，如受 platensimycin 启发的铬生物有机金属 PM47 所示。它将进一步作为具有未知作用机制的结构新颖的天然和合成抗菌化合物的参考特征。总之，我们在枯草芽孢杆菌中描述了一个由六个上调蛋白组成的蛋白质组学特征，该特征可诊断脂肪酸生物合成抑制，因此可用于推进抗菌药物发现计划。
