4,5-Disubstituted 6-Aryloxy-1,3-dihydrobenzo[c][1,2]oxaboroles Are Broad-Spectrum Serine β-Lactamase Inhibitors

详细信息    查看全文

• 作者：David C. McKinney ; Fei Zhou ; Charles J. Eyermann ; Andrew D. Ferguson ; D. Bryan Prince ; John Breen ; Robert A. Giacobbe ; Sushmita Lahiri ; Jeroen C. Verheijen
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：July 10, 2015
• 年：2015
• 卷：1
• 期：7
• 页码：310-316
• 全文大小：425K
• ISSN：2373-8227

文摘

Bacterially expressed β-lactamases are rapidly eroding the clinical utility of the important β-lactam class of antibacterials, significantly impairing our ability to fight serious bacterial infections. This paper describes a study of oxaborole-derived β-lactamase inhibitors in which crystal structures and computational modeling aided in the rational design of analogues with improved spectrum of activity against class A, C, and D enzymes. Crystal structures of two of these inhibitors covalently bound to two different serine β-lactamases, class C Pseudomonas aeruginosa AmpC and class D OXA-10, are described herein. Improved physicochemical properties as well as increased activity against an array of β-lactamases resulted in substantial restoration of susceptibility to ceftazidime in Escherichia coli and Klebsiella pneumoniae.