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Bicyclic boronates as potent inhibitors of AmpC, the class C β-Lactamase from Escherichia coli
Authors:
Pauline
Lang
(University of Oxford)
,
Anete
Parkova
(Latvian Institute of Organic Synthesis)
,
Thomas
Leissing
(University of Oxford)
,
Karina
Calvopina
(University of Oxford)
,
Ricky
Cain
(University of Leeds)
,
Alen
Krajnc
(University of Oxford)
,
Tharindi
Panduwawala
(University of Oxford)
,
Jules
Philippe
(Jacobs University Bremen gGmbH)
,
Colin W. G.
Fishwick
(University of Leeds)
,
Peteris
Trapencieris
(Latvian Institute of Organic Synthesis)
,
Malcolm
Page
(Jacobs University Bremen gGmbH)
,
Christopher J.
Schofield
(University of Oxford)
,
Jurgen
Brem
(University of Oxford)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Biomolecules
, VOL 10
State:
Published (Approved)
Published:
June 2020

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 coli, by bicyclic boronates, including taniborbactam, with different C-3 side chains. The combined studies reveal that an acylamino side chain is not essential for potent AmpC inhibition by active site binding bicyclic boronates. The tricyclic form of taniborbactam was observed bound to the surface of crystalline AmpC, but not at the active site, where the bicyclic form was observed. Structural comparisons reveal insights into why active site binding of a tricyclic form has been observed with the NDM-1 MBL, but not with other studied β-lactamases. Together with reported studies on the structural basis of inhibition of class A, B and D β‑lactamases, our data support the proposal that bicyclic boronates are broad-spectrum β‑lactamase inhibitors that work by mimicking a high energy ‘tetrahedral’ intermediate. These results suggest further SAR guided development could improve the breadth of clinically useful β-lactamase inhibition.
Journal Keywords: antibiotic resistance; β-lactam antibacterial; bicyclic boronate inhibitors; VNRX-5133/taniborbactam; vaborbactam; metallo- and serine-β-lactamase inhibition; transition state analogue
Diamond Keywords: Bacteria
Subject Areas:
Biology and Bio-materials,
Chemistry,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Added On:
17/06/2020 13:39
Documents:
biomolecules-10-00899.pdf
Discipline Tags:
Pathogens
Antibiotic Resistance
Infectious Diseases
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)