Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC.
Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan, ROC.
Bioorg Med Chem. 2022 Aug 1;67:116819. doi: 10.1016/j.bmc.2022.116819. Epub 2022 May 13.
A series of salicylanilide compounds was previously identified as antibacterial agents that inhibit the peptidoglycan formation. To find the exact binding mode, we synthesized a benzophenone-containing salicylanilide compound (1) and used it as a photoaffinity probe to label Acinetobacter baumannii penicillin-binding protein (PBP1b). After incubation and photo-irradiation, the labeled protein was subjected to trypsin digestion, dialysis enrichment, LC-ESI-MS/MS analysis, and Mascot search to reveal an octadecapeptide sequence RQLRTEYQESDLTNQGLR that was labeled at E372. Our molecular docking experiments suggest a hydrophobic pocket surrounded by R367 and E372 is the binding site of salicylanilide 1. The pocket lies in between the transglycosylase and transpeptidase domains, thus binding of salicylanilide 1 can block the propagation pathway to disrupt the growth of peptidoglycan chain.
先前已经鉴定出一系列柳酰苯胺类化合物是抑制肽聚糖形成的抗菌剂。为了找到确切的结合模式，我们合成了一种含有二苯甲酮的柳酰苯胺类化合物（1），并将其用作光亲和探针来标记鲍曼不动杆菌青霉素结合蛋白（PBP1b）。孵育和光照射后，对标记的蛋白质进行胰蛋白酶消化、透析富集、LC-ESI-MS/MS 分析和 Mascot 搜索，揭示了一个被标记在 E372 处的十八肽序列 RQLRTEYQESDLTNQGLR。我们的分子对接实验表明，由 R367 和 E372 环绕的疏水性口袋是柳酰苯胺 1 的结合位点。该口袋位于转糖基酶和转肽酶结构域之间，因此柳酰苯胺 1 的结合可以阻断肽聚糖链的生长途径，从而破坏其生长。
