1. Academic Validation
  2. High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes

High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes

  • J Med Chem. 2021 Aug 12;64(15):11379-11394. doi: 10.1021/acs.jmedchem.1c00717.
Hector Newman 1 2 Alen Krajnc 3 Dom Bellini 1 Charles J Eyermann 4 Grant A Boyle 4 Neil G Paterson 2 Katherine E McAuley 2 Robert Lesniak 3 Mukesh Gangar 4 Frank von Delft 2 5 6 7 Jürgen Brem 3 Kelly Chibale 4 8 Christopher J Schofield 3 Christopher G Dowson 1
Affiliations

Affiliations

  • 1 School of Life Sciences, University of Warwick, Coventry CV4 7AL, U.K.
  • 2 Diamond Light Source Ltd, Harwell Science and Innovation Campus, Didcot OX11 0DE, U.K.
  • 3 Department of Chemistry and the Ineos Oxford Institute of Antimicrobial Research, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.
  • 4 Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa.
  • 5 Structural Genomics Consortium (SGC), University of Oxford, Oxford, U.K.
  • 6 Department of Biochemistry, University of Johannesburg, Auckland Park 2006, South Africa.
  • 7 Research Complex at Harwell, Harwell Science and Innovation Campus, Didcot OX11 0FA, U.K.
  • 8 South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa.
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.

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