Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo-β-Lactamases
Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo-β-Lactamases
复制标题
DOI：
10.1002/cmdc.201900172
复制
发表时间：
2019-07-03
期刊：
影响因子：
3.4
通讯作者：
Cohen, Seth M.
中科院分区：
文献类型：
--
作者：
Chen, Allie Y.;Thomas, Pei W.;Cohen, Seth M.
新德里金属β-内酰胺酶-1（NDM-1）对我们最有效和最广泛的处方药--含β-内酰胺类抗生素--构成了直接威胁。目前还没有临床相关的抑制剂来对抗NDM-1，尽管在开发方面做出了巨大努力。使用羧酸基序结合NDM-1活性位点中的Zn-II离子的抑制剂占迄今报道的>500种抑制剂的大部分。迫切需要用于抑制剂开发的新的和结构多样的支架。本文报道了将吡啶二羧酸（DPA）的一个羧酸基团进行电子等排置换，得到对NDM-1（以及相关的金属β-内酰胺酶IMP-1和Vim-2）具有良好抑制活性的DPA电子等排体。已确定羧酸酯电子等排体的选择影响NDM-1抑制效力和作用机制。此外，我们表明，具有金属剥离机制的电子等排体可以被重新设计成有利于三元复合物形成的抑制剂。这项工作为未来常规使用的金属结合基序的等排替代提供了路线图（即，羧酸）用于在NDM-1抑制剂设计和开发中产生新实体。
New Delhi metallo-beta-lactamase-1 (NDM-1) poses an immediate threat to our most effective and widely prescribed drugs, the beta-lactam-containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM-1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the Zn-II ions in the active site of NDM-1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM-1 (and related metallo-beta-lactamases, IMP-1 and VIM-2). It was determined that the choice of carboxylate isostere influences both the potency of NDM-1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal-stripping mechanism can be re-engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM-1 inhibitor design and development.