Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.
Benzimidazole and Benzoxazole Zinc Chelators as Inhibitors of Metallo-β-Lactamase NDM-1.
复制标题
DOI：
10.1002/cmdc.202000607
复制
发表时间：
2021-02-17
期刊：
影响因子：
3.4
通讯作者：
Franz KJ
中科院分区：
文献类型：
--
作者：
Jackson AC;Pinter TBJ;Talley DC;Baker-Agha A;Patel D;Smith PJ;Franz KJ
水解β-内酰胺抗生素的β-内酰胺酶的细菌表达有助于增加抗菌药物耐药性的威胁。金属-β-内酰胺酶，如NDM-1，在其活性位点使用催化性锌离子并水解几乎所有临床可用的β-内酰胺抗生素。迫切需要金属-β-内酰胺酶的抑制剂来克服这种耐药机制。锌结合化合物是抑制剂开发的有希望的先导物，因为许多NDM-1抑制剂含有锌结合药效团。在这里，我们评估了十三个螯合剂含有苯并咪唑和苯并恶唑支架作为NDM-1抑制剂。其中6种化合物显示出有效的抑制活性，IC 50值低至0.38 μM，并且几种化合物恢复了表达NDM-1的E.杆菌光谱和对接研究表明三元复合物的形成作为抑制机制，使这些化合物有希望作为NDM-1抑制剂的发展。研究了锌结合苯并咪唑和苯并恶唑对临床重要的金属-β-内酰胺酶NDM-1的抑制作用，该酶可使几乎所有β-内酰胺抗生素失活。鉴定了几种强效抑制剂，其IC 50值低至0.38 μM。最佳化合物恢复了表达NDM-1的E.大肠杆菌转化为美罗培南。光谱和分子对接研究表明三元复合物的形成作为抑制机制。
Bacterial expression of β-lactamase enzymes that hydrolyze β-lactam antibiotics contributes to the growing threat of antibacterial drug resistance. Metallo-β-lactamases, such as NDM-1, use catalytic zinc ions in their active sites and hydrolyze nearly all clinically available β-lactam antibiotics. Inhibitors of metallo-β-lactamases are urgently needed to overcome this resistance mechanism. Zinc-binding compounds are promising leads for inhibitor development, as many NDM-1 inhibitors contain zinc-binding pharmacophores. Here, we evaluated thirteen chelating agents containing benzimidazole and benzoxazole scaffolds as NDM-1 inhibitors. Six of the compounds showed potent inhibitory activity with IC50 values as low as 0.38 μM, and several compounds restored meropenem susceptibility of NDM-1-expressing E. coli. Spectroscopic and docking studies suggest ternary complex formation as the mechanism of inhibition, making these compounds promising for development as NDM-1 inhibitors. Zinc-binding benzimidazoles and benzoxazoles were investigated for inhibition of the clinically important metallo-β-lactamase NDM-1, which inactivates nearly all β-lactam antibiotics. Several potent inhibitors were identified with IC50 values as low as 0.38 μM. Top compounds restored susceptibility of NDM-1-expressing E. coli to meropenem. Spectroscopic and molecular docking studies suggest ternary complex formation as the inhibition mechanism.
登录
查看更多内容
影响因子：
3.5
作者：
Huang, Shu-Ting;Hsei, I-Jen;Chen, Chinpiao
通讯作者：
Chen, Chinpiao
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
13.8
作者：
Ju LC;Cheng Z;Fast W;Bonomo RA;Crowder MW
通讯作者：
Crowder MW
影响因子：
4.9
作者：
OCALLAGHAN, CH;SHINGLER, AH;MORRIS, A
通讯作者：
MORRIS, A
影响因子：
1.8
作者：
RAO, AVR;YADAV, JS;UPENDER, V
通讯作者：
UPENDER, V