Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.
Department of Biology, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
Chemistry. 2021 Feb 19;27(11):3806-3811. doi: 10.1002/chem.202004694. Epub 2021 Jan 8.
The increasing prevalence of metallo-β-lactamase (MBL)-expressing bacteria presents a worrying trend in antibiotic resistance. MBLs rely on active site zinc ions for their hydrolytic activity and the pursuit of MBL-inhibitors has therefore involved the investigation of zinc chelators. To ensure that such chelators specifically target MBLs, a series of cephalosporin prodrugs of two potent zinc-binders: dipicolinic acid (DPA) and 8-thioquinoline (8-TQ) was prepared. Although both DPA and 8-TQ bind free zinc very tightly (K values in the low nm range), the corresponding cephalosporin conjugates do not. The cephalosporin conjugates are efficiently hydrolyzed by MBLs to release DPA or 8-TQ, as confirmed by using both NMR and LC-MS studies. Notably, the cephalosporin prodrugs of DPA and 8-TQ show potent inhibitory activity against NDM, VIM, and IMP classes of MBLs and display potent synergy with meropenem against MBL-expressing clinical isolates of K. pneumoniae and E. coli.
金属β-内酰胺酶（MBL）表达细菌的患病率不断上升，这是抗生素耐药性方面令人担忧的趋势。MBLs 依赖活性位点的锌离子发挥水解活性，因此，寻找 MBL 抑制剂的研究涉及锌螯合剂。为了确保这些螯合剂能够特异性地靶向 MBLs，我们制备了两种强效锌结合物：二吡啶酸（DPA）和 8-硫代喹啉（8-TQ）的头孢菌素前药。尽管 DPA 和 8-TQ 与游离锌结合非常紧密（K 值在低纳米范围内），但相应的头孢菌素缀合物却不能。通过使用 NMR 和 LC-MS 研究证实，头孢菌素缀合物可被 MBL 高效水解，释放出 DPA 或 8-TQ。值得注意的是，DPA 和 8-TQ 的头孢菌素前药对 NDM、VIM 和 IMP 类 MBL 具有很强的抑制活性，并与美罗培南对产 MBL 的肺炎克雷伯菌和大肠杆菌临床分离株表现出很强的协同作用。
