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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Biochemical characterization of an inhibitor of Escherichia coli UDP-N-acetylmuramyl--alanine ligase
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Biochemical characterization of an inhibitor of Escherichia coli UDP-N-acetylmuramyl--alanine ligase

机译：大肠杆菌UDP-N-乙酰基村acetyl基-丙氨酸连接酶抑制剂的生化特性

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摘要

UDP-N-acetylmuramyl--alanine ligase (MurC) is an essential bacterial enzyme involved in peptidoglycan biosynthesis and a target for the discovery of novel antibacterial agents. As a result of a high-throughput screen (HTS) against a chemical library for inhibitors of MurC, a series of benzofuran acyl-sulfonamides was identified as potential leads. One of these compounds, Compound A, inhibited Escherichia coli MurC with an IC50 of 2.3 M. Compound A exhibited time-dependent, partially reversible inhibition of E. coli MurC. Kinetic studies revealed a mode of inhibition consistent with the compound acting competitively with the MurC substrates ATP and UDP-N-acetyl-muramic acid (UNAM) with a Ki of 4.5 M against ATP and 6.3 M against UNAM. Fluorescence binding experiments yielded a Kd of 3.1 M for the compound binding to MurC. Compound A also exhibited high-affinity binding to bovine serum albumin (BSA) as evidenced by a severe reduction in MurC inhibition upon addition of BSA. This finding is consistent with the high lipophilicity of the compound. Advancement of this compound series for further drug development will require reduction of albumin binding.
机译：UDP-N-乙酰基muramyl-丙氨酸连接酶（MurC）是参与肽聚糖生物合成的必需细菌酶，也是发现新型抗菌剂的目标。针对针对MurC抑制剂的化学文库进行高通量筛选（HTS）的结果，一系列苯并呋喃酰基磺酰胺被确定为潜在的潜在客户。这些化合物之一，化合物A抑制大肠埃希氏菌MurC，IC50为2.3M。化合物A对大肠杆菌MurC表现出时间依赖性，部分可逆的抑制作用。动力学研究揭示了一种抑制模式，该抑制模式与该化合物与MurC底物ATP和UDP-N-乙酰基-山酰胺酸（UNAM）竞争性起作用，对ATP的Ki为4.5 M，对UNAM的Ki为6.3M。荧光结合实验得出该化合物与MurC结合的Kd为3.1M。化合物A还显示出与牛血清白蛋白（BSA）的高亲和力结合，这通过添加BSA后MurC抑制作用的严重降低来证明。该发现与该化合物的高亲脂性相一致。为了进一步的药物开发，该化合物系列的进展将需要减少白蛋白结合。

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