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Structure activity relationship studies on rhodanines and derived enethiol inhibitors of metallo-β-lactamases.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2018-02-23 , DOI: 10.1016/j.bmc.2018.02.043
Dong Zhang 1 , Marios S Markoulides 1 , Dmitrijs Stepanovs 1 , Anna M Rydzik 1 , Ahmed El-Hussein 2 , Corentin Bon 1 , Jos J A G Kamps 1 , Klaus-Daniel Umland 1 , Patrick M Collins 3 , Samuel T Cahill 1 , David Y Wang 1 , Frank von Delft 4 , Jürgen Brem 1 , Michael A McDonough 1 , Christopher J Schofield 1
Affiliation  

Metallo-β-lactamases (MBLs) enable bacterial resistance to almost all classes of β-lactam antibiotics. We report studies on enethiol containing MBL inhibitors, which were prepared by rhodanine hydrolysis. The enethiols inhibit MBLs from different subclasses. Crystallographic analyses reveal that the enethiol sulphur displaces the di-Zn(II) ion bridging 'hydrolytic' water. In some, but not all, cases biophysical analyses provide evidence that rhodanine/enethiol inhibition involves formation of a ternary MBL enethiol rhodanine complex. The results demonstrate how low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs and provide additional evidence for the potential of rhodanines to be hydrolysed to potent inhibitors of MBL protein fold and, maybe, other metallo-enzymes, perhaps contributing to the complex biological effects of rhodanines. The results imply that any medicinal chemistry studies employing rhodanines (and related scaffolds) as inhibitors should as a matter of course include testing of their hydrolysis products.

中文翻译:


金属-β-内酰胺酶绕丹宁及其衍生烯硫醇抑制剂的构效关系研究。



金属-β-内酰胺酶 (MBL) 使细菌对几乎所有类别的 β-内酰胺抗生素产生耐药性。我们报告了通过绕丹宁水解制备的含烯硫醇的 MBL 抑制剂的研究。烯硫醇抑制不同亚类的 MBL。晶体分析表明,烯硫醇硫取代了桥接“水解”水的二锌 (II) 离子。在某些(但不是全部)情况下,生物物理分析提供证据表明绕丹宁/烯硫醇抑制涉及三元 MBL 烯硫醇绕丹宁复合物的形成。结果证明低分子量活性位点 Zn(II) 螯合化合物如何抑制一系列临床相关的 MBL,并为绕丹宁水解为 MBL 蛋白折叠以及其他金属酶的有效抑制剂的潜力提供了额外的证据,也许有助于绕丹宁​​的复杂生物效应。结果意味着任何使用绕丹宁(和相关支架)作为抑制剂的药物化学研究当然应该包括对其水解产物的测试。
更新日期:2018-02-23
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