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.
Highlights
The effectiveness of β-lactam antibiotics is increasingly compromised by β-lactamases
To create the peptidoglycan mesh essential for bacterial survival.[3,4] β-Lactams inhibit penicillin-binding protein (PBP), initially by competing with the D-Ala-D-Ala terminus of the stem peptide substrate to give a non-covalent complex, which reacts with the activesite catalytic serine [in Pseudomonas aeruginosa PBP3 (PaPBP3): Ser294] to give an acyl−enzyme complex which is stable over a biologically relevant timescale.[5]
Vaborbactam forms a covalent bond reacting with the catalytic serine, whereas the benzoxaboroles form dicovalent complexes, and the boronic acids form tricovalent complexes
Summary
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. In Gram-negative bacteria, inhibition of high-molecular mass (HMM) class A and class B PBPs (PBP1a/b, PBP2, and PBP3) is typically lethal.[1,2] The class B PBP3 is a monofunctional peptidoglycan transpeptidase, which is associated with cell division, where it cross-links stem peptides of polymerized molecules of lipid II to create the peptidoglycan mesh essential for bacterial survival.[3,4] β-Lactams inhibit PBPs, initially by competing with the D-Ala-D-Ala terminus of the stem peptide substrate to give a non-covalent complex, which reacts with the activesite catalytic serine [in Pseudomonas aeruginosa PBP3 (PaPBP3): Ser294] to give an acyl−enzyme complex which is stable over a biologically relevant timescale.[5]
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