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PDBsum entry 4hef
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Hydrolase/hydrolase inhibitor
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PDB id
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4hef
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References listed in PDB file
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Key reference
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Title
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Structural insight into potent broad-Spectrum inhibition with reversible recyclization mechanism: avibactam in complex with ctx-M-15 and pseudomonas aeruginosa ampc β-Lactamases.
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Authors
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S.D.Lahiri,
S.Mangani,
T.Durand-Reville,
M.Benvenuti,
F.De luca,
G.Sanyal,
J.D.Docquier.
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Ref.
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Antimicrob Agents Chemother, 2013,
57,
2496-2505.
[DOI no: ]
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PubMed id
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Abstract
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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.
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