Optimization of amino acid thioesters as inhibitors of metallo-beta-lactamase L1
Optimization of amino acid thioesters as inhibitors of metallo-beta-lactamase L1
复制标题
氨基酸硫酯作为金属-β-内酰胺酶 L1 抑制剂的优化
DOI：
10.1016/j.bmcl.2016.08.048
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发表时间：
2016
影响因子：
2.7
通讯作者：
Oelschlaeger Peter
中科院分区：
文献类型：
--
作者：
Liu Xiao Long;Yang Ke Wu;Zhang Yue Juan;Ge Ying;Xiang Yang;Chang Ya Nan;Oelschlaeger Peter
金属β-内酰胺酶（MβLs）引起的抗生素耐药性的出现是一个全球性的公共卫生问题。最近，我们发现氨基酸硫酯是一种非常有前途的m - β ll1抑制剂支架。为了优化这一系列抑制剂，通过对硫酯的n端取代基和代表氨基酸侧链的基团进行修饰，开发了9种新的氨基酸硫酯。生物活性测定表明，它们都是非常有效的L1抑制剂，ic50值范围为20-600 nM，低于之前报道的大多数该支架抑制剂。构效关系分析表明，n端大疏水取代基和蛋氨酸氨基酸侧链提高了硫酯的抑制活性。所有这些抑制剂都能恢复β-内酰胺类抗生素对大肠杆菌bl21 （DE3）细胞的抑菌活性，这些细胞产生L1。缺乏β-内酰胺酶的结肠细胞。对接研究表明，较大的n端疏水性基团与相同位置较小的疏水性基团的结合模式略有不同。
The emergence of antibiotic resistance caused by metallo-β-lactamases (MβLs) is a global public health problem. Recently, we found amino acid thioesters to be a highly promising scaffold for inhibitors of the MβL L1. In order to optimize this series of inhibitors, nine new amino acid thioesters were developed by modifying the substituents on the N-terminus of the thioesters and the groups representing the amino acid side chain. Biological activity assays indicate that all of them are very potent inhibitors of L1 with an IC50value range of 20–600 nM, lower than those of most of the previously reported inhibitors of this scaffold. Analysis of structure–activity relationship reveals that big hydrophobic substituents on the N-terminus and a methionine amino acid side chain improves inhibitory activity of the thioesters. All these inhibitors are able to restore antibacterial activity of a β-lactam antibiotic againstEscherichia coliBL21(DE3) cells producing L1 to that againstE. colicells lacking a β-lactamase. Docking studies reveal that a large N-terminal hydrophobic group results in a slightly different binding mode than smaller hydrophobic groups at the same position.