Avibactam and Class C β-Lactamases: Mechanism of Inhibition, Conservation of the Binding Pocket, and Implications for Resistance
Open Access
- 1 October 2014
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 58 (10), 5704-5713
- https://doi.org/10.1128/aac.03057-14
Abstract
Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits a wide range of β-lactamases. These include class A, class C, and some class D enzymes, which erode the activity of β-lactam drugs in multidrug-resistant pathogens like Pseudomonas aeruginosa and Enterobacteriaceae spp. Avibactam is currently in clinical development in combination with the β-lactam antibiotics ceftazidime, ceftaroline fosamil, and aztreonam. Avibactam has the potential to be the first β-lactamase inhibitor that might provide activity against class C-mediated resistance, which represents a growing concern in both hospital- and community-acquired infections. Avibactam has an unusual mechanism of action: it is a covalent inhibitor that acts via ring opening, but in contrast to other currently used β-lactamase inhibitors, this reaction is reversible. Here, we present a high-resolution structure of avibactam bound to a class C β-lactamase, AmpC, from P. aeruginosa that provided insight into the mechanism of both acylation and recyclization in this enzyme class and highlighted the differences observed between class A and class C inhibition. Furthermore, variants resistant to avibactam that identified the residues important for inhibition were isolated. Finally, the structural information was used to predict effective inhibition by sequence analysis and functional studies of class C β-lactamases from a large and diverse set of contemporary clinical isolates (P. aeruginosa and several Enterobacteriaceae spp.) obtained from recent infections to understand any preexisting variability in the binding pocket that might affect inhibition by avibactam.Keywords
This publication has 36 references indexed in Scilit:
- “Stormy waters ahead”: global emergence of carbapenemasesFrontiers in Microbiology, 2013
- New antibiotics for bad bugs: where are we?Annals of Clinical Microbiology and Antimicrobials, 2013
- Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitorProceedings of the National Academy of Sciences, 2012
- In Vitro Antibacterial Activity of the Ceftazidime-Avibactam (NXL104) Combination against Pseudomonas aeruginosa Clinical IsolatesAntimicrobial Agents and Chemotherapy, 2012
- Increasing prevalence and dissemination of NDM-1 metallo- -lactamase in India: data from the SMART study (2009)Journal of Antimicrobial Chemotherapy, 2011
- Mechanistic Studies of the Inactivation of TEM-1 and P99 by NXL104, a Novel Non-β-Lactam β-Lactamase InhibitorAntimicrobial Agents and Chemotherapy, 2010
- Molecular Basis for Drug Resistance in HIV-1 ProteaseViruses, 2010
- Extended-Spectrum Cephalosporinases in Pseudomonas aeruginosaAntimicrobial Agents and Chemotherapy, 2009
- Re‐examining the role of Lys67 in class C β‐lactamase catalysisProtein Science, 2009
- AmpC β-LactamasesClinical Microbiology Reviews, 2009