Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, D-60438 Frankfurt, Germany.
Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Straße 40, D-60596 Frankfurt, Germany.
Molecules. 2023 Feb 20;28(4):1984. doi: 10.3390/molecules28041984.
Metallo beta lactamases (MBLs) are among the most problematic resistance mechanisms of multidrug-resistant Gram-negative pathogens due to their broad substrate spectrum and lack of approved inhibitors. In this study, we propose the integration of catechol substructures into the design of thiol-based MBL inhibitors, aiming at mimicking bacterial siderophores for the active uptake by the iron acquisition system of bacteria. We synthesised two catechol-containing MBL inhibitors, as well as their dimethoxy counterparts, and tested them for in vitro inhibitory activity against NDM-1, VIM-1, and IMP-7. We demonstrated that the most potent catechol-containing MBL inhibitor is able to bind Fe ions. Finally, we could show that this compound restores the antibiotic activity of imipenem in NDM-1-expressing , while leaving HUVEC cells completely unaffected. Thus, siderophore-containing MBL inhibitors might be a valuable strategy to overcome bacterial MBL-mediated resistance to beta lactam antibiotics.
金属β-内酰胺酶（MBLs）是多药耐药革兰氏阴性病原体中最成问题的耐药机制之一，因为它们具有广泛的底物谱和缺乏批准的抑制剂。在这项研究中，我们提出将儿茶酚结构整合到基于硫醇的 MBL 抑制剂的设计中，旨在模拟细菌的铁载体，以便通过细菌的铁摄取系统进行主动摄取。我们合成了两种含有儿茶酚的 MBL 抑制剂及其二甲氧基对应物，并测试了它们对 NDM-1、VIM-1 和 IMP-7 的体外抑制活性。我们证明，最有效的含儿茶酚的 MBL 抑制剂能够结合 Fe 离子。最后，我们能够表明该化合物恢复了在 NDM-1 表达的情况下亚胺培南的抗生素活性，而对 HUVEC 细胞完全没有影响。因此，含有铁载体的 MBL 抑制剂可能是克服细菌 MBL 介导的β-内酰胺抗生素耐药性的一种有价值的策略。
