title: Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases.
abstract: Although β-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 β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-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 β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class C Pseudomonas aeruginosa AmpC β-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.
authors: Infection Biosciences, AstraZeneca R&D Boston, Waltham, Massachusetts, USA.
authors: Sushmita D
authors: SD
authors: Lahiri
authors: Stefano
authors: S
authors: Mangani
authors: Thomas
authors: T
authors: Durand-Reville
authors: Manuela
authors: M
authors: Benvenuti
authors: Filomena
authors: F
authors: De Luca
authors: Gautam
authors: G
authors: Sanyal
authors: Jean-Denis
authors: JD
authors: Docquier
mesh_terms: D000215:Acylation; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D053961:Azabicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D003460:Crystallization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry* / Q000378:metabolism; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001426:Bacterial Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; C543519:avibactam; C473109:beta-lactamase CTX-M-15; C048795:AmpC beta-lactamases; D001618:beta-Lactamases