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PDBsum entry 4zam
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Hydrolase/hydrolase inhibitor
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PDB id
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4zam
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References listed in PDB file
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Key reference
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Title
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Inhibition of klebsiella β-Lactamases (shv-1 and kpc-2) by avibactam: a structural study.
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Authors
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N.P.Krishnan,
N.Q.Nguyen,
K.M.Papp-Wallace,
R.A.Bonomo,
F.Van den akker.
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Ref.
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Plos One, 2015,
10,
e0136813.
[DOI no: ]
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PubMed id
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Abstract
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β-Lactamase inhibition is an important clinical strategy in overcoming
β-lactamase-mediated resistance to β-lactam antibiotics in Gram negative
bacteria. A new β-lactamase inhibitor, avibactam, is entering the clinical
arena and promising to be a major step forward in our antibiotic armamentarium.
Avibactam has remarkable broad-spectrum activity in being able to inhibit
classes A, C, and some class D β-lactamases. We present here structural
investigations into class A β-lactamase inhibition by avibactam as we report
the crystal structures of SHV-1, the chromosomal penicillinase of Klebsiella
pneumoniae, and KPC-2, an acquired carbapenemase found in the same pathogen,
complexed with avibactam. The 1.80 Å KPC-2 and 1.42 Å resolution SHV-1
β-lactamase avibactam complex structures reveal avibactam covalently bonded to
the catalytic S70 residue. Analysis of the interactions and chair-shaped
conformation of avibactam bound to the active sites of KPC-2 and SHV-1 provides
structural insights into recently laboratory-generated amino acid substitutions
that result in resistance to avibactam in KPC-2 and SHV-1. Furthermore, we
observed several important differences in the interactions with amino acid
residues, in particular that avibactam forms hydrogen bonds to S130 in KPC-2 but
not in SHV-1, that can possibly explain some of the different kinetic constants
of inhibition. Our observations provide a possible reason for the ability of
KPC-2 β-lactamase to slowly desulfate avibactam with a potential role for the
stereochemistry around the N1 atom of avibactam and/or the presence of an active
site water molecule that could aid in avibactam desulfation, an unexpected
consequence of novel inhibition chemistry.
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