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.
Keywords: Gram-negative infections; oxaboroles; structure-guided design; β-lactamase inhibitors.