McKinney, David C, Zhou, Fei, Eyermann, Charles J, Ferguson, Andrew D, Prince, D Bryan, Breen, John, Giacobbe, Robert A, 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