Department of Urology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China; Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA.
Trends Pharmacol Sci. 2018 Jul;39(7):635-647. doi: 10.1016/j.tips.2018.03.007. Epub 2018 Apr 18.
Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.
金属β-内酰胺酶（MBLs）是一个重大的临床问题，因为它们能水解并使几乎所有含β-内酰胺的抗生素失活。这些“救命药”占现有当代抗生素武器库的>50%。尽管 MBL 在全球范围内传播，但 MBL 抑制剂尚未出现在临床试验中。大多数 MBL 抑制剂针对活性位点锌离子，其机制从三元复合物形成到金属离子剥夺不等。重要的是，机制的差异可能会影响药理学方面的可逆性、靶标选择性和结构-活性关系解释。本综述调查了 MBL 抑制剂的机制，并描述了确定抑制机制的方法，以指导未来治疗药物的开发。
