Molecular Mechanism of Avibactam-Mediated β-Lactamase Inhibition.
Emerging β-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the β-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine β-lactamases than has been previously observed with β-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D β-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine β-lactamases. Herein, we reveal the 1.7- and 2.0-Å-resolution crystal structures of avibactam covalently bound to class D β-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A β-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated β-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.
The Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia , 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Dustin T
DT
King
M. G. Department of Biochemistry and Biomedical Sciences and the Department of Chemistry, DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
Andrew M
AM
King
M. G. Department of Biochemistry and Biomedical Sciences and the Department of Chemistry, DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
Sarah M
SM
Lal
M. G. Department of Biochemistry and Biomedical Sciences and the Department of Chemistry, DeGroote Institute for Infectious Disease Research, McMaster University , Hamilton, Ontario L8S 4K1, Canada.
Gerard D
GD
Wright
The Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia , 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Natalie C J
NC
Strynadka
avibactam; inhibition; β-Lactamase