Instituto de Biología Molecular y Celular de Rosario (IBR, CONICET-UNR), Ocampo and Esmeralda, Rosario S2002LRK, Argentina.
Laboratorio de Química Farmacéutica, Facultad de Química, Universidad de la Republica (UdelaR), Montevideo 11800, Uruguay.
Biomolecules. 2020 Jun 3;10(6):854. doi: 10.3390/biom10060854.
β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.
β-内酰胺类抗生素由于其低毒性和广谱性而被广泛用于临床。然而，细菌会通过不同的耐药机制来对抗β-内酰胺类抗生素的作用。其中，最常见的策略是表达β-内酰胺酶，这些酶能够水解所有β-内酰胺化合物中的酰胺键。目前已经有一些针对丝氨酸-β-内酰胺酶（SBLs）的抑制剂。金属β-内酰胺酶（MBLs）是一类依赖 Zn(II)的酶，能够水解大多数β-内酰胺类抗生素，目前还没有临床可用的针对它们的抑制剂获得批准。尽管 MBLs 具有很大的结构多样性，但它们具有相似的反应物种的共同催化机制。在这里，我们描述了一些模拟水解过程中形成的不同物种的 MBL 抑制剂：底物、过渡态、中间产物或产物。本文还讨论了螯合剂作为一种可能的策略的应用，因为 Zn(II)离子对于底物结合和催化是必不可少的。
