School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia.
School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia.
Bioorg Med Chem Lett. 2023 Aug 15;92:129387. doi: 10.1016/j.bmcl.2023.129387. Epub 2023 Jun 25.
Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ∼65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against prominent representatives of the MBL family. Several compounds are potent inhibitors of each MBL tested, making them promising candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL family, with K values in the low µM range. Furthermore, this compound also appears to display synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents a promising starting point to develop new drugs to inhibit a major mechanism of antibiotic resistance.
金属β-内酰胺酶（MBLs）是一组依赖 Zn(II)的酶，对全球健康构成重大威胁。它们与越来越多的多药耐药细菌病原体有关，但目前还没有临床有效的抑制剂。由于 MBLs 使β-内酰胺抗生素失活，而β-内酰胺抗生素约占用于治疗感染的所有抗生素的 65%，因此迫切需要寻找具有临床相关性的 MBL 抑制剂。在此，合成了 2-氨基-1-苄基-4,5-二苯基-1H-吡咯-3-甲腈（1a）的衍生物，并评估了它们对 MBL 家族主要代表的抑制作用。几种化合物对每种测试的 MBL 都是有效的抑制剂，使它们成为开发广谱药物先导物的有希望的候选物。特别是，化合物 5f 对 MBL 家族具有很高的活性，其 K 值在低µM 范围内。此外，该化合物与青霉素 G、头孢呋辛或美罗培南等抗生素联合使用时似乎也表现出协同作用。因此，该分子代表了开发抑制抗生素耐药主要机制的新药的有前途的起点。
