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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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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Oxa-48 in complex with fpi-1465
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Structure:
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Beta-lactamase. Chain: a, b. Engineered: yes
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Source:
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Klebsiella pneumoniae. Organism_taxid: 573. Gene: bla oxa-48, blaoxa-48, kpe71t_00045. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.96Å
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R-factor:
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0.170
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R-free:
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0.210
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Authors:
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A.M.King,D.T.King,S.French,E.Brouillette,A.Asli,A.N.Alexander, M.Vuckovic,S.N.Maiti,T.R.Parr,E.D.Brown,F.Malouin,N.C.J.Strynadka, G.D.Wright
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Key ref:
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A.M.King
et al.
(2016).
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins.
Acs Chem Biol,
11,
864-868.
PubMed id:
DOI:
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Date:
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11-Dec-15
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Release date:
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20-Jan-16
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PROCHECK
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Headers
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References
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Q6XEC0
(Q6XEC0_KLEPN) -
Beta-lactamase from Klebsiella pneumoniae
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Seq:
Struc:
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265 a.a.
241 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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DOI no:
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Acs Chem Biol
11:864-868
(2016)
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PubMed id:
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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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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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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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Links
