Clinically-relevant β-lactamases: Structure-function relationships and inhibition.

β-lactamases are important resistance factors to β-lactam antibiotics, especially in Gram-negative bacteria, that show an extraordinary diversity in terms of structure, mechanism of hydrolysis and substrate profile and susceptibility to inhibitors. Two families of β-lactamases are currently known: (a) the active site serine β-lactamases which perform hydrolysis of β-lactams via an acylation-deacylation mechanism and (b) the metallo-β-lactamases, which require one or two zinc ion(s) for activity. The current knowledge on β-lactamase structure-function relationships will be reviewed, with a particular focus on carbapenemases, such as KPC-2, VIM-2 and NDM-1 metallo-β-lactamases and OXA-type carbapenem-hydrolyzing enzymes, which currently represent among the most worrisome resistance determinants currently emerging in Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae. The identification and development of new β-lactamase inhibitors, whose clinical need is stronger than ever, is an active field of research. The properties of novel β-lactamase inhibitors, some of which are under clinical development (e. g. NXL104), will be discussed.