The prevalence of infections caused by metallo-β-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all β-lactam antibiotics, there are as of yet no approved drugs available that inhibit their activity. We here examine the ability of previously reported thiol-based MBL inhibitors to synergize with meropenem and cefoperazone against a panel of Gram-negative carbapenem-resistant isolates expressing different β-lactamases. Among the compounds tested, thiomandelic acid 3 and 2-mercapto-3-phenylpropionic acid 4 were found to efficiently potentiate the activity of meropenem, especially against an imipenemase (IMP) producing strain of K. pneumoniae. In light of the zinc-dependent hydrolytic mechanism employed by MBLs, biophysical studies using isothermal titration calorimetry were also performed, revealing a correlation between the synergistic activity of thiols 3 and 4 and their zinc-binding ability with measured K_d values of 9.8 and 20.0 μM, respectively.

中文翻译：

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含硫醇的金属-β-内酰胺酶抑制剂使耐药革兰氏阴性菌对美洛培南敏感

近年来，由表达金属-β-内酰胺酶（MBL）的革兰氏阴性细菌引起的感染流行以惊人的速度增长。尽管事实上MBL可以使几乎所有的β-内酰胺类抗生素失活，但迄今为止尚无批准的抑制其活性的药物。我们在这里检查了以前报道的基于硫醇的MBL抑制剂与美罗培南和头孢哌酮对一组表达不同β-内酰胺酶的革兰氏阴性碳青霉烯耐药菌株的协同作用。在测试的化合物中，发现硫代扁桃酸3和2-巯基-3-苯基丙酸4能有效增强美罗培南的活性，特别是针对产生亚胺培南酶（IMP）的肺炎克雷伯菌菌株。。根据MBL所使用的锌依赖性水解机制，还进行了使用等温滴定量热法的生物物理研究，揭示了硫醇3和4的协同活性与其锌结合能力之间的相关性，测得的K _d值为9.8和20.0。分别为μM。