High-Throughput Crystallography Reveals Boron-Containing Inhibitors of a Penicillin-Binding Protein with Di- and Tricovalent Binding Modes
Hector Newman, Alen Krajnc, Dom Bellini, Charles J. Eyermann, Grant A. Boyle, Neil G. Paterson, Katherine McAuley, Robert K. Leśniak, Mukesh Gangar, F. von Delft, Jürgen Brem, Kelly Chibale, Christopher J. Schofield, Christopher G. Dowson
Abstract
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.