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High-throughput crystallography reveals boron-containing inhibitors of a penicillin-binding protein with di- and tricovalent binding modes

DOI: 10.1021/acs.jmedchem.1c00717 DOI Help

Authors: Hector Newman (University of Warwick; Diamond Light Source) , Alen Krajnc (University of Oxford) , Domenico Bellini (University of Warwick) , Charles J. Eyermann (University of Cape Town) , Grant A. Boyle (University of Cape Town) , Neil Paterson (Diamond Light Source) , Katherine E. Mcauley (Diamond Light Source) , Robert Lesniak (University of Oxford) , Mukesh Gangar (University of Cape Town) , Frank Von Delft (Diamond Light Source; Structural Genomics Consortium (SGC), University of Oxford; University of Johannesburg; Research Complex at Harwell) , Jurgen Brem (University of Oxford) , Kelly Chibale (University of Cape Town) , Christopher J. Schofield (University of Oxford) , Christopher G. Dowson (University of Warwick)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 64

State: Published (Approved)
Published: July 2021
Diamond Proposal Number(s): 17884

Open Access Open Access

Abstract: The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases. Boron-containing inhibitors are potent serine-β-lactamase inhibitors, but the interactions of boron-based compounds with the penicillin-binding protein (PBP) β-lactam targets have not been extensively studied. We used high-throughput X-ray crystallography to explore reactions of a boron-containing fragment set with the Pseudomonas aeruginosa PBP3 (PaPBP3). Multiple crystal structures reveal that boronic acids react with PBPs to give tricovalently linked complexes bonded to Ser294, Ser349, and Lys484 of PaPBP3; benzoxaboroles react with PaPBP3 via reaction with two nucleophilic serines (Ser294 and Ser349) to give dicovalently linked complexes; and vaborbactam reacts to give a monocovalently linked complex. Modifications of the benzoxaborole scaffold resulted in a moderately potent inhibition of PaPBP3, though no antibacterial activity was observed. Overall, the results further evidence the potential for the development of new classes of boron-based antibiotics, which are not compromised by β-lactamase-driven resistance.

Journal Keywords: Binding modes; Chemical structure; Assays; Inhibitors; Inhibition

Diamond Keywords: Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 02/08/2021 08:42

Documents:
acs.jmedchem.1c00717.pdf

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Antibiotic Resistance Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening