Interplay between β-lactamases and new β-lactamase inhibitors

Resistance to beta-lactann antibiotics in Gram-negative bacteria is commonly associated with production of beta-lactannases, including extended-spectrum beta-lactannases (ESBLs) and carbapenemases belonging to different molecular classes: those with a catalytically active serine and those with at least one active-site Zre' to facilitate hydrolysis. To counteract the hydrolytic activity of these enzymes, combinations of a beta-lactann with a beta-lactannase inhibitor (BLI) have been clinically successful. However, some beta-lactann BLI combinations have lost their effectiveness against prevalent Gram-negative pathogens that produce ESBLs, carbapenemases or multiple beta-lactannases in the same organism. In this Review, descriptions are provided for medically relevant beta-lactannase families and various BLI combinations that have been developed or are under development. Recently approved inhibitor combinations include the inhibitors avibactann and vaborbactam of the diazabicyclooctanone and boronic acid inhibitor classes, respectively, as new scaffolds for future inhibitor design.