4,5-Disubstituted 6-Aryloxy-1,3-dihydrobenzo[c][1,2]oxaboroles Are Broad-Spectrum Serine β-Lactamase Inhibitors.
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.
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
David C
DC
McKinney
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
Fei
F
Zhou
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
Charles J
CJ
Eyermann
Andrew D
AD
Ferguson
D Bryan
DB
Prince
John
J
Breen
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
Robert A
RA
Giacobbe
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
Sushmita
S
Lahiri
Infection Innovative Medicines, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham Massachusetts 02451, United States.
Jeroen C
JC
Verheijen
Gram-negative infections; oxaboroles; structure-guided design; β-lactamase inhibitors