Dockerty Paul, Edens Jerre G, Tol Menno B, Morales Angeles Danae, Domenech Arnau, Liu Yun, Hirsch Anna K H, Veening Jan-Willem, Scheffers Dirk-Jan, Witte Martin D
Chemical Biology, Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
Molecular Microbiology, Groningen Institute for Biomolecular Sciences and Biotechnology, University of Groningen, Nijenborgh 7, 9747AG Groningen, The Netherlands.
Org Biomol Chem. 2017 Jan 25;15(4):894-910. doi: 10.1039/c6ob01664b.
Natural products form attractive leads for the development of chemical probes and drugs. The antibacterial lipopeptide Brabantamide A contains an unusual enol cyclocarbamate and we used this scaffold as inspiration for the synthesis of a panel of enol cyclocarbamate containing compounds. By equipping the scaffold with different groups, we identified structural features that are essential for antibacterial activity. Some of the derivatives block incorporation of hydroxycoumarin carboxylic acid-amino d-alanine into the newly synthesized peptidoglycan. Activity-based protein-profiling experiments revealed that the enol carbamates inhibit a specific subset of penicillin-binding proteins in B. subtilis and S. pneumoniae.
天然产物为化学探针和药物的开发提供了有吸引力的先导化合物。抗菌脂肽布拉班酰胺A含有一种不寻常的烯醇环氨基甲酸酯，我们以此支架为灵感合成了一系列含烯醇环氨基甲酸酯的化合物。通过在支架上连接不同的基团，我们确定了对抗菌活性至关重要的结构特征。一些衍生物可阻止羟基香豆素羧酸 - 氨基 - D - 丙氨酸掺入新合成的肽聚糖中。基于活性的蛋白质谱分析实验表明，烯醇氨基甲酸酯可抑制枯草芽孢杆菌和肺炎链球菌中特定子集的青霉素结合蛋白。
