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PDBsum entry 5faq
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Hydrolase/hydrolase inhibitor
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PDB id
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5faq
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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 and kinetic characterization of diazabicyclooctanes as dual inhibitors of both serine-β-Lactamases and penicillin-Binding proteins.
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Authors
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A.M.King,
D.T.King,
S.French,
E.Brouillette,
A.Asli,
J.A.Alexander,
M.Vuckovic,
S.N.Maiti,
T.R.Parr,
E.D.Brown,
F.Malouin,
N.C.Strynadka,
G.D.Wright.
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Ref.
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Acs Chem Biol, 2016,
11,
864-868.
[DOI no: ]
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PubMed id
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Abstract
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Avibactam is a diazabicyclooctane β-lactamase inhibitor possessing outstanding
but incomplete efficacy against multidrug-resistant Gram-negative pathogens in
combination with β-lactam antibiotics. Significant pharmaceutical investment in
generating derivatives of avibactam warrants a thorough characterization of
their activity. We show here through structural and kinetic analysis that select
diazabicyclooctane derivatives display effective but varied inhibition of two
clinically important β-lactamases (CTX-M-15 and OXA-48). Furthermore, these
derivatives exhibit considerable antimicrobial activity (MIC ≤ 2 μg/mL)
against clinical isolates of Pseudomonas aeruginosa, Escherichia coli, and
Enterobacter spp. Imaging of cell phenotype along with structural and
biochemical experiments unambiguously demonstrate that this activity, in E.
coli, is a result of targeting penicillin-binding protein 2. Our results suggest
that structure-activity relationship studies for the purpose of drug discovery
must consider both β-lactamases and penicillin-binding proteins as targets. We
believe that this approach will yield next-generation combination or
monotherapies with an expanded spectrum of activity against currently
untreatable Gram-negative pathogens.
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