2020
DOI: 10.3390/biom10060899
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Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli

Abstract: Resistance to β-lactam antibacterials, importantly via production of β-lactamases, threatens their widespread use. Bicyclic boronates show promise as clinically useful, dual-action inhibitors of both serine- (SBL) and metallo- (MBL) β-lactamases. In combination with cefepime, the bicyclic boronate taniborbactam is in phase 3 clinical trials for treatment of complicated urinary tract infections. We report kinetic and crystallographic studies on the inhibition of AmpC, the class C β-lactamase from Escherichia co… Show more

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Cited by 24 publications
(33 citation statements)
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“…Steady-state competitive inhibition kinetics of AmpC EC by AVI, REL, NAC, and ZID were measured using the fluorescent substrate FC-5 ( 33 ) and analyzed as previously described ( 34 ). All the tested DBOs were potent inhibitors for AmpC EC , with apparent inhibition constant ( K iapp ) values ranging from 7.4 μM for AVI to 0.69 μM for ZID.…”
Section: Resultsmentioning
confidence: 99%
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“…Steady-state competitive inhibition kinetics of AmpC EC by AVI, REL, NAC, and ZID were measured using the fluorescent substrate FC-5 ( 33 ) and analyzed as previously described ( 34 ). All the tested DBOs were potent inhibitors for AmpC EC , with apparent inhibition constant ( K iapp ) values ranging from 7.4 μM for AVI to 0.69 μM for ZID.…”
Section: Resultsmentioning
confidence: 99%
“…To investigate the basis for the kinetics observed for ZID compared to other DBOs against AmpC EC , structures of AmpC EC in complex with AVI (1.51 Å resolution; PDB entry 6TBW ), REL (1.72 Å resolution; PDB entry 6TPM ), NAC (1.47 Å resolution; PDB entry 6T7L ), and ZID (1.30 Å resolution; PDB entry 6T5Y ) were solved. The complexes were obtained using relatively short (10- to 15-min) inhibitor soakings of AmpC EC crystals, which were produced as reported previously ( 34 ). In all cases, there was one protein molecule in each asymmetric unit; structures were solved by molecular replacement, using the reported AmpC EC structure (PDB entry 6T3D [ 34 ]).…”
Section: Resultsmentioning
confidence: 99%
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