Bicyclic boronates as potent inhibitors of AmpC, the class C β-Lactamase from Escherichia coli

DOI: 10.3390/biom10060899

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)