Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition
Rhodanine hydrolysis leads to potent thioenolate mediated metallo-β-lactamase inhibition
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DOI：
10.1038/nchem.2110
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发表时间：
2014-12-01
期刊：
影响因子：
21.8
通讯作者：
Schofield, Christopher J.
中科院分区：
文献类型：
--
作者：
Brem, Juergen;van Berkel, Sander S.;Schofield, Christopher J.
β-内酰胺抗生素的使用受到耐药性的影响，耐药性由属于金属（MBL）-和丝氨酸（SBL）-β-内酰胺酶亚家族的β-内酰胺酶提供。罗丹宁是抑制青霉素结合蛋白（PBP）、SBL和最近报道的MBL的极少数化合物类别之一。在这里，我们描述了晶体学分析的机制，抑制临床相关的Vim-2 MBL的绕丹宁，这表明绕丹宁环进行水解，得到一个硫代烯醇化物。发现硫代烯醇盐通过二锌螯合结合，模拟β-内酰胺水解中中间体的结合。Vim-2在完整的若丹宁存在下结晶导致观察到MBL、硫代烯醇化物片段和若丹宁的三元复合物。晶体学观察得到了动力学和生物物理研究的支持，包括F-19 NMR分析，其揭示了若丹宁衍生的硫代烯醇盐是一种有效的广谱MBL抑制剂，并且是开发新型临床有用的MBL抑制剂的先导结构。
The use of beta-lactam antibiotics is compromised by resistance, which is provided by beta-lactamases belonging to both metallo (MBL)- and serine (SBL)-beta-lactamase subfamilies. The rhodanines are one of very few compound classes that inhibit penicillin-binding proteins (PBPs), SBLs and, as recently reported, MBLs. Here, we describe crystallographic analyses of the mechanism of inhibition of the clinically relevant VIM-2 MBL by a rhodanine, which reveal that the rhodanine ring undergoes hydrolysis to give a thioenolate. The thioenolate is found to bind via di-zinc chelation, mimicking the binding of intermediates in beta-lactam hydrolysis. Crystallization of VIM-2 in the presence of the intact rhodanine led to observation of a ternary complex of MBL, a thioenolate fragment and rhodanine. The crystallographic observations are supported by kinetic and biophysical studies, including F-19 NMR analyses, which reveal the rhodanine-derived thioenolate to be a potent broad-spectrum MBL inhibitor and a lead structure for the development of new types of clinically useful MBL inhibitors.