Discovery of Novel Inhibitor Scaffolds against the Metallo-β-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening
Discovery of Novel Inhibitor Scaffolds against the Metallo-β-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening
复制标题
DOI：
10.1021/acs.jmedchem.5b01289
复制
发表时间：
2015-11-12
影响因子：
7.3
通讯作者：
Leiros, Hanna-Kirsti S.
中科院分区：
文献类型：
--
作者：
Christopeit, Tony;Carlsen, Trine Josefine O.;Leiros, Hanna-Kirsti S.
金属β-内酰胺酶(MBL)抑制剂可以恢复碳青霉烯类抗生素的功能，从而有助于治疗耐药细菌的感染。在这项研究中，我们报告了抑制临床相关的MBL Verona整合子编码的金属β-内酰胺酶(VIM-2)的新片段。使用基于表面等离子体共振(SPR)结合酶抑制试验的正交筛选方法从490个片段的文库中鉴定这些片段。识别出的碎片的IC50值在14-1500微米之间，配基效率(LE)在0.48-0.23千卡/摩尔/重原子之间。对鉴定的两个片段，得到了与VIM-2形成的络合物的晶体结构。鉴定的片段代表了新型的抑制剂支架，是设计有效的MBL抑制剂的良好起点。此外，建立的基于SPR的分析和筛选方法可以适用于其他MBL，从而改进这类重要药物靶点的药物发现过程。
Metallo-beta-lactamase (MBL) inhibitors can restore the function of carbapenem antibiotics and therefore help to treat infections of antibiotic resistant bacteria. In this study, we report novel fragments inhibiting the clinically relevant MBL Verona integron-encoded metallo-beta-lactamase (VIM-2). The fragments were identified from a library of 490 fragments using an orthogonal screening approach based on a surface plasmon resonance (SPR) based assay combined with an enzyme inhibition assay. The identified fragments showed IC50 values between 14 and 1500 mu M and ligand efficiencies (LE) between 0.48 and 0.23 kcal/mol per heavy atom. For two of the identified fragments, crystal structures in complex with VIM-2 were obtained. The identified fragments represent novel inhibitor scaffolds and are good starting points for the design of potent MBL inhibitors. Furthermore, the established SPR based assay and the screening approach can be adapted to other MBLs and in this way improve the drug discovery process for this important class of drug targets.