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

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 highthroughput X-ray crystallography to explore reactions of a boroncontaining 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.

Visible-light-driven PhSSPh-catalysed regioselective hydroborylation of α,β-unsaturated carbonyl compounds with NHC-boranes

“…As we all know, organoboron compounds play an important role in synthetic organic chemistry, and they are versatile and powerful building blocks for cross–coupling reactions. 1 In addition, organoboron compounds have also attracted significant attention in catalysis, 2 the pharmaceutical industry 3 and materials science 4 recently. Among the numerous boron-containing compounds, α-boryl carbonyl compounds that feature two reaction centers: a boryl group and a carbonyl moiety are very useful synthons.…”

Molecular docking analysis and evaluation of the antimicrobial properties of the constituents of Geranium wallichianum D. Don ex Sweet from Kashmir Himalaya

“…As part of this process, the PBPs help to create the morphology of the peptidoglycan exoskeleton together with cytoskeleton proteins that regulate septum formation and cell shape. Many natural compounds were reported to inhibit the synthesis of PBP 58 , 59 . Interestingly, elatine and kaempherol showed highest binding affinities as compared to already known natural inhibitors against PBP.…”

Structural analysis of the boronic acid β-lactamase inhibitor vaborbactam binding to Pseudomonas aeruginosa penicillin-binding protein 3

“…Although zidebactam can bind PBP3, it prefers to inhibit PBP2 through which it mediates its "enhancer" properties [13,15,18]. Very recently, another group has also determined the structure of P. aeruginosa PBP3 bound to vaborbactam ( [47]; PDB id 7AUH). The vaborbactam PBP3 interactions in this analysis show only a single conformation of the aminothiazole ring (inspection of the temperature factors of the 7AUH coordinates also revealed the same trend as we have described).…”