Liénard Benoît M R, Garau Gianpiero, Horsfall Louise, Karsisiotis Andreas I, Damblon Christian, Lassaux Patricia, Papamicael Cyril, Roberts Gordon C K, Galleni Moreno, Dideberg Otto, Frère Jean-Marie, Schofield Christopher J
Chemistry Research Laboratory and OCISB, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.
Org Biomol Chem. 2008 Jul 7;6(13):2282-94. doi: 10.1039/b802311e. Epub 2008 May 7.
The development of broad-spectrum metallo-beta-lactamase (MBL) inhibitors is challenging due to structural diversity and differences in metal utilisation by these enzymes. Analysis of structural data, followed by non-denturing mass spectrometric analyses, identified thiols proposed to inhibit representative MBLs from all three sub-classes: B1, B2 and B3. Solution analyses led to the identification of broad spectrum inhibitors, including potent inhibitors of the CphA MBL (Aeromonas hydrophila). Structural studies revealed that, as observed for other B1 and B3 MBLs, inhibition of the L1 MBL thiols involves metal chelation. Evidence is reported that this is not the case for inhibition of the CphA enzyme by some thiols; the crystal structure of the CphA-Zn-inhibitor complex reveals a binding mode in which the thiol does not interact with the zinc. The structural data enabled the design and the production of further more potent inhibitors. Overall the results suggest that the development of reasonably broad-spectrum MBL inhibitors should be possible.
由于这些酶的结构多样性以及金属利用方式的差异，开发广谱金属β-内酰胺酶（MBL）抑制剂具有挑战性。对结构数据进行分析，随后进行非变性质谱分析，确定了一些硫醇，这些硫醇被认为可以抑制来自所有三个亚类（B1、B2和B3）的代表性MBL。溶液分析导致了广谱抑制剂的鉴定，包括嗜水气单胞菌CphA MBL的强效抑制剂。结构研究表明，正如在其他B1和B3 MBL中观察到的那样，L1 MBL硫醇的抑制涉及金属螯合。有证据表明，某些硫醇对CphA酶的抑制并非如此；CphA-锌-抑制剂复合物的晶体结构揭示了一种结合模式，其中硫醇不与锌相互作用。这些结构数据有助于设计和生产更有效的抑制剂。总体而言，结果表明开发合理的广谱MBL抑制剂应该是可行的。
