Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, California 94025, United States.
ACS Infect Dis. 2021 May 14;7(5):1164-1176. doi: 10.1021/acsinfecdis.0c00714. Epub 2021 Jan 3.
Avibactam is a potent diazobicyclooctane inhibitor of class A and C β-lactamases. The inhibitor also exhibits variable activity against some class D enzymes from Gram-negative bacteria; however, its interaction with recently discovered class D β-lactamases from Gram-positive bacteria has not been studied. Here, we describe microbiological, kinetic, and mass spectrometry studies of the interaction of avibactam with CDD-1, a class D β-lactamase from the clinically important pathogen , and show that avibactam is a potent irreversible mechanism-based inhibitor of the enzyme. X-ray crystallographic studies at three time-points demonstrate the rapid formation of a stable CDD-1-avibactam acyl-enzyme complex and highlight differences in the anchoring of the inhibitor by class D enzymes from Gram-positive and Gram-negative bacteria.
阿维巴坦是一种强效的二氮杂二环辛烷抑制剂，属于 A 类和 C 类β-内酰胺酶。该抑制剂对革兰氏阴性菌的一些 D 类酶也具有可变的活性；然而，其与最近从革兰氏阳性菌中发现的 D 类β-内酰胺酶的相互作用尚未被研究。在这里，我们描述了阿维巴坦与 CDD-1（一种来自临床重要病原体 的 D 类β-内酰胺酶）相互作用的微生物学、动力学和质谱研究，并表明阿维巴坦是该酶的一种强效的不可逆的基于机制的抑制剂。三个时间点的 X 射线晶体学研究表明，快速形成稳定的 CDD-1-阿维巴坦酰化酶复合物，并突出了革兰氏阳性菌和革兰氏阴性菌的 D 类酶对抑制剂的锚定的差异。
