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PDBsum entry 3d4f
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References listed in PDB file
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Key reference
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Title
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Strategic design of an effective {beta}-Lactamase inhibitor: ln-1-255, A 6-Alkylidene-2'-Substituted penicillin sulfone.
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Authors
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P.Pattanaik,
C.R.Bethel,
A.M.Hujer,
K.M.Hujer,
A.M.Distler,
M.Taracila,
V.E.Anderson,
T.R.Fritsche,
R.N.Jones,
S.R.Pagadala,
F.Van den akker,
J.D.Buynak,
R.A.Bonomo.
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Ref.
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J Biol Chem, 2009,
284,
945-953.
[DOI no: ]
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PubMed id
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Abstract
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In an effort to devise strategies for overcoming bacterial beta-lactamases, we
studied LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone inhibitor. By
possessing a catecholic functionality that resembles a natural bacterial
siderophore, LN-1-255 is unique among beta-lactamase inhibitors. LN-1-255
combined with piperacillin was more potent against Escherichia coli DH10B
strains bearing bla(SHV) extended-spectrum and inhibitor-resistant
beta-lactamases than an equivalent amount of tazobactam and piperacillin. In
addition, LN-1-255 significantly enhanced the activity of ceftazidime and
cefpirome against extended-spectrum cephalosporin and Sme-1 containing
carbapenem-resistant clinical strains. LN-1-255 inhibited SHV-1 and SHV-2
beta-lactamases with nm affinity (K(I) = 110 +/- 10 and 100 +/- 10 nm,
respectively). When LN-1-255 inactivated SHV beta-lactamases, a single
intermediate was detected by mass spectrometry. The crystal structure of
LN-1-255 in complex with SHV-1 was determined at 1.55A resolution.
Interestingly, this novel inhibitor forms a bicyclic aromatic intermediate with
its carbonyl oxygen pointing out of the oxyanion hole and forming hydrogen bonds
with Lys-234 and Ser-130 in the active site. Electron density for the "tail" of
LN-1-255 is less ordered and modeled in two conformations. Both conformations
have the LN-1-255 carboxyl group interacting with Arg-244, yet the remaining
tails of the two conformations diverge. The observed presence of the bicyclic
aromatic intermediate with its carbonyl oxygen positioned outside of the
oxyanion hole provides a rationale for the stability of this inhibitory
intermediate. The 2'-substituted penicillin sulfone, LN-1-255, is proving to be
an important lead compound for novel beta-lactamase inhibitor design.
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Figure 1.
Chemical structures of the β-lactamase inhibitors. A,
general structure of 7-alkylidene-3-substituted cephalosporin
sulfones. B, general structure of 6-alkylidene-2′-substituted
penicillin sulfones. C, LN-1-255. D, tazobactam sodium.
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Figure 8.
Proposed mechanism of enzymatic inhibition by the
6-(pyridylmethylidene)penicillin sulfone series of inhibitors.
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The above figures are
reprinted
from an Open Access publication published by the ASBMB:
J Biol Chem
(2009,
284,
945-953)
copyright 2009.
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