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

McKinney, David C and Zhou, Fei and Eyermann, Charles J and Ferguson, Andrew D and Prince, D Bryan and Breen, John and Giacobbe, Robert A and Lahiri, S and Verheijen, Jeroen (2015) 4,5-di-Substituted 6-Aryloxy-1,3-dihydrobenzo[c][1,2]oxaboroles are Broad-Spectrum Serine β-Lactamase Inhibitors. ACS Infectious Diseases, 1 (7). pp. 310-316. ISSN 2373-82272373-8227

Abstract

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 report describes a study of oxaborole-derived β-lactamase inhibitors where crystal structures and computational modeling aided in the rational design of analogs 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.

Item Type: Article
Keywords: Oxaboroles, beta-lactamase inhibitors, Gram-negative infections, Structure-guided design
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/25089

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