Andersson Hanna, Jarvoll Patrik, Yang Shao-Kang, Yang Ke-Wu, Erdélyi Máté
Department of Chemistry-BMC, Uppsala University, P.O. Box 576, SE-751 23 Uppsala, Sweden.
Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden.
ACS Omega. 2020 Aug 18;5(34):21570-21578. doi: 10.1021/acsomega.0c02187. eCollection 2020 Sep 1.
Metallo-β-lactamase (MBL)-producing bacteria resistant to β-lactam antibiotics are a serious threat to human health. Despite great efforts and important progress in the discovery of MBL inhibitors (MBLIs), there is none in clinical use. Herein, inhibitor complexes of the MBL CcrA were investigated by NMR spectroscopy to provide perspectives on the further development of 2-(triazolylthio)acetamide-type MBLIs. By using the NMR-based chemical shift perturbation (CSP) and direction of CSP methodologies together with molecular docking, the spatial orientation of three compounds in the CcrA active site was investigated (). Inhibitor showed the best binding affinity ( ≈ 2.3 ± 0.3 μM), followed by ( = 11 ± 11 μM) and ( = 34 ± 43 μM), as determined from the experimental NMR data. Based on the acquired knowledge, analogues of other MBLIs () were designed and evaluated with the purpose of examining a strategy for promoting their interactions with the catalytic zinc ions.
产金属β-内酰胺酶（MBL）且对β-内酰胺类抗生素耐药的细菌对人类健康构成严重威胁。尽管在发现MBL抑制剂（MBLIs）方面付出了巨大努力并取得了重要进展，但目前尚无临床应用的MBLIs。本文通过核磁共振波谱法研究了MBL CcrA的抑制剂复合物，为2-(三唑基硫代)乙酰胺型MBLIs的进一步开发提供参考。通过基于核磁共振的化学位移扰动（CSP）和CSP方向方法以及分子对接，研究了三种化合物在CcrA活性位点的空间取向。根据实验核磁共振数据确定，抑制剂表现出最佳的结合亲和力（Kd≈2.3±0.3μM），其次是（Kd = 11±11μM）和（Kd = 34±43μM）。基于所获得的知识，设计并评估了其他MBLIs的类似物，目的是研究促进它们与催化锌离子相互作用的策略。
