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PDBsum entry 4x6t
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Hydrolase/hydrolase inhibitor
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PDB id
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4x6t
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References listed in PDB file
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Key reference
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Title
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Inhibiting the β-Lactamase of mycobacterium tuberculosis (mtb) with novel boronic acid transition-State inhibitors (batsis).
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Authors
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S.G.Kurz,
S.Hazra,
C.R.Bethel,
C.Romagnoli,
E.Caselli,
F.Prati,
J.S.Blanchard,
R.A.Bonomo.
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Ref.
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ACS Infect Dis, 2015,
1,
234-242.
[DOI no: ]
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PubMed id
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Abstract
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BlaC, the single chromosomally encoded β-lactamase of Mycobacterium
tuberculosis, has been identified as a promising target for novel therapies that
rely upon β-lactamase inhibition. Boronic acid transition-state inhibitors
(BATSIs) are a class of β-lactamase inhibitors which permit rational inhibitor
design by combinations of various R1 and R2 side chains. To explore the
structural determinants of effective inhibition, we screened a panel of 25
BATSIs to explore key structure-function relationships. We identified a
cefoperazone analogue, EC19, which displayed slow, time-dependent inhibition
against BlaC with a potency similar to that of clavulanate (Ki* of 0.65 ± 0.05
μM). To further characterize the molecular basis of inhibition, we solved the
crystallographic structure of the EC19-BlaC(N172A) complex and expanded our
analysis to variant enzymes. The results of this structure-function analysis
encourage the design of a novel class of β-lactamase inhibitors, BATSIs, to be
used against Mycobacterium tuberculosis.
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