Profiling interactions of vaborbactam with metallo-β-lactamases

[Display omitted] β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that...

Full description

Saved in:

Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (15), p.1981-1984
Main Authors:	Langley, Gareth W., Cain, Ricky, Tyrrell, Jonathan M., Hinchliffe, Philip, Calvopiña, Karina, Tooke, Catherine L., Widlake, Emma, Dowson, Christopher G., Spencer, James, Walsh, Timothy R., Schofield, Christopher J., Brem, Jürgen
Format:	Article
Language:	eng
Subjects:	Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Antibiotic resistance beta-Lactamases - pharmacology beta-Lactamases - therapeutic use Boronate inhibitor Boronic Acids - pharmacology Boronic Acids - therapeutic use Humans Serine- and metallo-β-lactamase Transition state analogue Vaborbactam β-Lactamase induction
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	[Display omitted] β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups: the serine β-lactamases that utilise a covalent acyl-enzyme mechanism and the metallo β-lactamases that utilise a zinc-bound water nucleophile. Achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Vaborbactam has recently been approved for clinical use in combination with the carbapenem meropenem. Here we show that vaborbactam moderately inhibits metallo-β-lactamases from all 3 subclasses (B1, B2 and B3), with a potency of around 20–100 fold below that by which it inhibits its current clinical targets, the Class A serine β-lactamases. This result contrasts with recent investigations of bicyclic boronate inhibitors, which potently inhibit subclass B1 MBLs but which presently lack activity against B2 and B3 enzymes. These findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of β-lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors.
ISSN:	0960-894X 1464-3405