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

• Published in: ACS infectious diseases Vol. 1; no. 7; pp. 310 - 316
• Main Authors: McKinney, David C, Zhou, Fei, Eyermann, Charles J, Ferguson, Andrew D, Prince, D. Bryan, Breen, John, Giacobbe, Robert A, Lahiri, Sushmita, Verheijen, Jeroen C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-07-2015
• Subjects: β-lactamase inhibitors; oxaboroles; Gram-negative infections; structure-guided design
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.5b00031

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.