Shin Woo Shik, Bergstrom Alexander, Bonomo Robert A, Crowder Michael W, Muthyala Ramaiah, Sham Yuk Yin
Center for Drug Design & Bioinformatics and Computational Biology, Program, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Chemistry and Biochemistry, Miami University, Oxford, OH, 45056, USA.
ChemMedChem. 2017 Jun 7;12(11):845-849. doi: 10.1002/cmdc.201700182. Epub 2017 May 22.
VIM-2 is one of the most common carbapenem-hydrolyzing metallo β-lactamases (MBL) found in many drug-resistant Gram-negative bacterial strains. Currently, there is a lack of effective lead compounds with optimal therapeutic potential within our drug development pipeline. Here we report the discovery of 1-hydroxypyridine-2(1H)-thione-6-carboxylic acid (3) as a first-in-class metallo β-lactamase inhibitor (MBLi) with a potent inhibition K of 13 nm against VIM-2 that corresponds to a remarkable 0.99 ligand efficiency. We further established that 3 can restore the antibiotic activity of amoxicillin against VIM-2-producing E. coli in a whole cell assay with an EC of 110 nm. The potential mode of binding of 3 from molecular modeling provided structural insights that could corroborate the observed changes in the biochemical activities. Finally, 3 possesses a low cytotoxicity (CC ) of 97 μm with a corresponding therapeutic index of 880, making it a promising lead candidate for further optimization in combination antibacterial therapy.
VIM-2是在许多耐药革兰氏阴性菌菌株中发现的最常见的碳青霉烯水解金属β-内酰胺酶（MBL）之一。目前，在我们的药物研发流程中，缺乏具有最佳治疗潜力的有效先导化合物。在此，我们报告发现1-羟基吡啶-2（1H）-硫酮-6-羧酸（3）作为一类新型金属β-内酰胺酶抑制剂（MBLi），其对VIM-2的抑制常数K为13 nm，对应显著的0.99配体效率。我们进一步证实，在全细胞实验中，3可以恢复阿莫西林对产VIM-2大肠杆菌的抗生素活性，其半数效应浓度（EC）为110 nm。分子模拟得出的3的潜在结合模式提供了结构见解，能够证实所观察到的生化活性变化。最后，3具有97 μm的低细胞毒性（CC），相应的治疗指数为880，使其成为联合抗菌治疗中进一步优化的有前景的先导候选物。
