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PDBsum entry 1a8t
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Antibiotic sensitization using biphenyl tetrazoles as potent inhibitors of bacteroides fragilis metallo-Beta-Lactamase.
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Authors
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J.H.Toney,
P.M.Fitzgerald,
N.Grover-Sharma,
S.H.Olson,
W.J.May,
J.G.Sundelof,
D.E.Vanderwall,
K.A.Cleary,
S.K.Grant,
J.K.Wu,
J.W.Kozarich,
D.L.Pompliano,
G.G.Hammond.
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Ref.
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Chem Biol, 1998,
5,
185-196.
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PubMed id
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Abstract
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BACKGROUND: High level resistance to carbapenem antibiotics in gram negative
bacteria such as Bacteroides fragilis is caused, in part, by expression of a
wide-spectrum metallo-beta-lactamase that hydrolyzes the drug to an inactive
form. Co-administration of metallo-beta-lactamase inhibitors to resistant
bacteria is expected to restore the antibacterial activity of carbapenems.
RESULTS: Biphenyl tetrazoles (BPTs) are a structural class of potent competitive
inhibitors of metallo-beta-lactamase identified through screening and predicted
using molecular modeling of the enzyme structure. The X-ray crystal structure of
the enzyme bound to the BPT L-159,061 shows that the tetrazole moiety of the
inhibitor interacts directly with one of the two zinc atoms in the active site,
replacing a metal-bound water molecule. Inhibition of metallo-beta-lactamase by
BPTs in vitro correlates well with antibiotic sensitization of resistant B.
fragilis. CONCLUSIONS: BPT inhibitors can sensitize a resistant B. fragilis
clinical isolate expressing metallo-beta-lactamase to the antibiotics imipenem
or penicillin G but not to rifampicin.
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Secondary reference #1
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Title
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Unanticipated inhibition of the metallo-Beta-Lactamase from bacteroides fragilis by 4-Morpholineethanesulfonic acid (mes): a crystallographic study at 1.85-A resolution.
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Authors
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P.M.Fitzgerald,
J.K.Wu,
J.H.Toney.
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Ref.
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Biochemistry, 1998,
37,
6791-6800.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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High-Yield expression, Purification, And characterization of active, Soluble bacteroides fragilis metallo-Beta-Lactamase, Ccra.
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Authors
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J.H.Toney,
J.K.Wu,
K.M.Overbye,
C.M.Thompson,
D.L.Pompliano.
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Ref.
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Protein Expr Purif, 1997,
9,
355-362.
[DOI no: ]
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PubMed id
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