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PDBsum entry 5evd
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References listed in PDB file
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Key reference
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Title
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Cross-Class metallo-β-Lactamase inhibition by bisthiazolidines reveals multiple binding modes.
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Authors
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P.Hinchliffe,
M.M.González,
M.F.Mojica,
J.M.González,
V.Castillo,
C.Saiz,
M.Kosmopoulou,
C.L.Tooke,
L.I.Llarrull,
G.Mahler,
R.A.Bonomo,
A.J.Vila,
J.Spencer.
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Ref.
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Proc Natl Acad Sci U S A, 2016,
113,
E3745.
[DOI no: ]
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PubMed id
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Abstract
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Metallo-β-lactamases (MBLs) hydrolyze almost all β-lactam antibiotics and are
unaffected by clinically available β-lactamase inhibitors (βLIs). Active-site
architecture divides MBLs into three classes (B1, B2, and B3), complicating
development of βLIs effective against all enzymes. Bisthiazolidines (BTZs) are
carboxylate-containing, bicyclic compounds, considered as penicillin analogs
with an additional free thiol. Here, we show both l- and d-BTZ enantiomers are
micromolar competitive βLIs of all MBL classes in vitro, with Kis of 6-15 µM
or 36-84 µM for subclass B1 MBLs (IMP-1 and BcII, respectively), and 10-12 µM
for the B3 enzyme L1. Against the B2 MBL Sfh-I, the l-BTZ enantiomers exhibit
100-fold lower Kis (0.26-0.36 µM) than d-BTZs (26-29 µM). Importantly,
cell-based time-kill assays show BTZs restore β-lactam susceptibility of
Escherichia coli-producing MBLs (IMP-1, Sfh-1, BcII, and GOB-18) and,
significantly, an extensively drug-resistant Stenotrophomonas maltophilia
clinical isolate expressing L1. BTZs therefore inhibit the full range of MBLs
and potentiate β-lactam activity against producer pathogens. X-ray crystal
structures reveal insights into diverse BTZ binding modes, varying with
orientation of the carboxylate and thiol moieties. BTZs bind the di-zinc centers
of B1 (IMP-1; BcII) and B3 (L1) MBLs via the free thiol, but orient differently
depending upon stereochemistry. In contrast, the l-BTZ carboxylate dominates
interactions with the monozinc B2 MBL Sfh-I, with the thiol uninvolved. d-BTZ
complexes most closely resemble β-lactam binding to B1 MBLs, but feature an
unprecedented disruption of the D120-zinc interaction. Cross-class MBL
inhibition therefore arises from the unexpected versatility of BTZ binding.
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