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
