Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Division of Cell Biology, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
J Med Chem. 2021 Jul 8;64(13):9141-9151. doi: 10.1021/acs.jmedchem.1c00362. Epub 2021 Jun 28.
In an attempt to exploit the hydrolytic mechanism by which β-lactamases degrade cephalosporins, we designed and synthesized a series of novel cephalosporin prodrugs aimed at delivering thiol-based inhibitors of metallo-β-lactamases (MBLs) in a spatiotemporally controlled fashion. While enzymatic hydrolysis of the β-lactam ring was observed, it was not accompanied by inhibitor release. Nonetheless, the cephalosporin prodrugs, especially thiomandelic acid conjugate (), demonstrated potent inhibition of IMP-type MBLs. In addition, conjugate was also found to greatly reduce the minimum inhibitory concentration of meropenem against IMP-producing bacteria. The results of kinetic experiments indicate that these prodrugs inhibit IMP-type MBLs by acting as slowly turned-over substrates. Structure-activity relationship studies revealed that both phenyl and carboxyl moieties of are crucial for its potency. Furthermore, modeling studies indicate that productive interactions of the thiomandelic acid moiety of with Trp28 within the IMP active site may contribute to its potency and selectivity.
为了利用β-内酰胺酶降解头孢菌素的水解机制，我们设计并合成了一系列新型头孢菌素前药，旨在以时空控制的方式递送基于硫醇的金属β-内酰胺酶（MBL）抑制剂。虽然观察到β-内酰胺环的酶水解，但没有伴随抑制剂释放。尽管如此，头孢菌素前药，特别是硫代扁桃酸共轭物（），对 IMP 型 MBL 表现出很强的抑制作用。此外，还发现共轭物可大大降低产 IMP 的细菌对美罗培南的最小抑菌浓度。动力学实验结果表明，这些前药通过充当缓慢转化的底物来抑制 IMP 型 MBL。构效关系研究表明，共轭物的苯和羧基部分对于其效力都是至关重要的。此外，建模研究表明，与 IMP 活性位点中的 Trp28 进行生产性相互作用可能有助于其效力和选择性。
