Smith Clyde A, Antunes Nuno Tiago, Stewart Nichole K, Toth Marta, Kumarasiri Malika, Chang Mayland, Mobashery Shahriar, Vakulenko Sergei B
Stanford Synchrotron Radiation Lightsource, Stanford University, Menlo Park, CA 94025, USA.
Chem Biol. 2013 Sep 19;20(9):1107-15. doi: 10.1016/j.chembiol.2013.07.015. Epub 2013 Sep 5.
Dissemination of Acinetobacter baumannii strains harboring class D β-lactamases producing resistance to carbapenem antibiotics severely limits our ability to treat deadly Acinetobacter infections. Susceptibility determination in the A. baumannii background and kinetic studies with a homogeneous preparation of OXA-23 β-lactamase, the major carbapenemase present in A. baumannii, document the ability of this enzyme to manifest resistance to last-resort carbapenem antibiotics. We also report three X-ray structures of OXA-23: apo OXA-23 at two different pH values, and wild-type OXA-23 in complex with meropenem, a carbapenem substrate. The structures and dynamics simulations reveal an important role for Leu166, whose motion regulates the access of a hydrolytic water molecule to the acyl-enzyme species in imparting carbapenemase activity.
携带D类β-内酰胺酶且对碳青霉烯类抗生素产生耐药性的鲍曼不动杆菌菌株的传播，严重限制了我们治疗致命鲍曼不动杆菌感染的能力。在鲍曼不动杆菌背景下进行的药敏试验以及对鲍曼不动杆菌中主要碳青霉烯酶OXA-23β-内酰胺酶的纯化物进行的动力学研究，证明了这种酶对作为最后手段的碳青霉烯类抗生素产生耐药性的能力。我们还报告了OXA-23的三种X射线结构：两种不同pH值下的无配体OXA-23，以及与碳青霉烯底物美罗培南结合的野生型OXA-23。这些结构和动力学模拟揭示了Leu166的重要作用，其运动调节水解水分子进入酰基酶物种以赋予碳青霉烯酶活性。
