Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates

• Published in: Nature communications 2016-08, Vol.7 (1), p.12406-12406, Article 12406
• Main Authors: Brem, Jürgen, Cain, Ricky, Cahill, Samuel, McDonough, Michael A., Clifton, Ian J., Jiménez-Castellanos, Juan-Carlos, Avison, Matthew B., Spencer, James, Fishwick, Colin W. G., Schofield, Christopher J.
• Format: Article
• Language: English
• Subjects: 631/45/535; 639/638/92/607; 82/47; 82/83; beta-Lactamases - chemistry; beta-Lactamases - metabolism; Boronic Acids - chemistry; Boronic Acids - pharmacology; Cyclization; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HEK293 Cells; Humanities and Social Sciences; Humans; Microbial Sensitivity Tests; multidisciplinary; Penicillin-Binding Proteins - antagonists & inhibitors; Penicillin-Binding Proteins - metabolism; Science; Science (multidisciplinary); Serine - metabolism; Structure-Activity Relationship
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12406

β-Lactamases enable resistance to almost all β-lactam antibiotics. Pioneering work revealed that acyclic boronic acids can act as ‘transition state analogue’ inhibitors of nucleophilic serine enzymes, including serine-β-lactamases. Here we report biochemical and biophysical analyses revealing that cyclic boronates potently inhibit both nucleophilic serine and zinc-dependent β-lactamases by a mechanism involving mimicking of the common tetrahedral intermediate. Cyclic boronates also potently inhibit the non-essential penicillin-binding protein PBP 5 by the same mechanism of action. The results open the way for development of dual action inhibitors effective against both serine- and metallo-β-lactamases, and which could also have antimicrobial activity through inhibition of PBPs. Bacterial beta-lactamases are responsible for resistance to beta-lactams, the most important family of antibiotics. Here, the authors reveal cyclic boronate inhibitors that are active against both serine- and metallo-beta-lactamases and represent a promising strategy for combined antimicrobial treatments.