Department of Physiology, University of Hong Kong, Hong Kong, China.
FASEB J. 2011 Aug;25(8):2574-82. doi: 10.1096/fj.11-184036. Epub 2011 Apr 20.
Metallo-β-lactamases (MBLs) hydrolyze most β-lactam antibiotics, and bacteria containing this kind of enzyme pose a serious threat to the public health. The newly identified New Delhi MBL (NDM-1) is a new member of this family that shows tight binding to penicillin and cephalosporins. The rapid dissemination of NDM-1 in clinically relevant bacteria has become a global concern. However, no clinically useful inhibitors against MBLs exist, partly due to the lack of knowledge about the catalysis mechanism of this kind of enzyme. Here we report the crystal structure of this novel enzyme in complex with a hydrolyzed ampicillin at its active site at 1.3-Å resolution. Structural comparison with other MBLs revealed a new hydrolysis mechanism applicable to all three subclasses of MBLs, which might help the design of mechanism based inhibitors.
金属β-内酰胺酶（MBLs）可水解大多数β-内酰胺类抗生素，携带此类酶的细菌对公共健康构成严重威胁。新发现的新德里金属β-内酰胺酶（NDM-1）是该家族的一个新成员，它与青霉素和头孢菌素具有紧密的结合能力。NDM-1 在临床相关细菌中的迅速传播已成为全球关注的问题。然而，目前尚无针对 MBL 的临床有效抑制剂，部分原因是对这种酶的催化机制缺乏了解。在此，我们报道了该新型酶与活性位点中已水解的氨苄青霉素复合物的晶体结构，分辨率为 1.3Å。与其他 MBL 的结构比较揭示了一种适用于所有三类 MBL 的新水解机制，这可能有助于基于机制的抑制剂的设计。
