Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases.
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Lahiri SD, Mangani S, Durand-Reville T, Benvenuti M, De Luca F, Sanyal G, Docquier JD
Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC beta-lactamases.
Antimicrob Agents Chemother. 2013 Jun;57(6):2496-505. doi: 10.1128/AAC.02247-12. Epub 2013 Feb 25.
- PubMed ID
- 23439634 [ View in PubMed]
- Abstract
Although beta-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of beta-lactamase enzymes that are not affected by currently marketed beta-lactam/beta-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-beta-lactam beta-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D beta-lactamases. Here we describe the structures of two clinically important beta-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum beta-lactamase and the class C Pseudomonas aeruginosa AmpC beta-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.