Molecular Mechanism of Avibactam-Mediated β-Lactamase Inhibition

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• 作者：Dustin T. King ; Andrew M. King ; Sarah M. Lal ; Gerard D. Wright ; Natalie C. J. Strynadka
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：April 10, 2015
• 年：2015
• 卷：1
• 期：4
• 页码：175-184
• 全文大小：431K
• ISSN：2373-8227

文摘

Emerging β-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the β-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine β-lactamases than has been previously observed with β-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D β-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine β-lactamases. Herein, we reveal the 1.7- and 2.0-Å-resolution crystal structures of avibactam covalently bound to class D β-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A β-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated β-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.