What is it about?
β-Lactamases are the most important mechanism of resistance to the β-lactam antibacterials. There are two mechanistic classes of β-lactamases – the serine β-lactamases (SBLs) and the zinc-dependent metallo-β-lactamases (MBLs). Avibactam, the first clinically useful non-β-lactam β-lactamase inhibitor, is a broad-spectrum SBL inhibitor, which is used in combination with a cephalosporin antibiotic (ceftazidime). There are multiple reports on the interaction of avibactam with SBLs, but few such studies with MBLs. We report biochemical and biophysical studies on the binding and reactivity of avibactam with representatives from all 3 MBL subfamilies (B1, B2 and B3). Avibactam only has limited or no activity vs. MBL-mediated resistance in pathogens. Avibactam does not inhibit MBLs and binds only weakly to most of the MBLs tested; in some cases, avibactam undergoes slow hydrolysis of one of its urea N-CO bonds followed by loss of CO2, in a process different from that observed with studied SBLs. The results suggest that whilst the evolution of MBLs that more efficiently catalyze avibactam hydrolysis should be anticipated, pursuing the development of dual action SBL and MBL inhibitors based on the diazabicyclooctane core of avibactam may be productive
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Why is it important?
The susceptibility of avibactam to MBL catalyzed hydrolysis has not yet been reported. This is an important issue since MBLs are becoming more widespread, and MBL-catalyzed avibactam hydrolysis has the potential to impair the potency of β-lactam antibiotic-avibactam combinations against strains producing both SBLs and MBLs. Here, we report that avibactam is not an MBL inhibitor and a poor substrate of most members of all three clinically relevant subclasses of MBLs. The results suggest that whilst the evolution of MBLs that more effectively catalyze avibactam hydrolysis should be anticipated, the development of dual action SBL and MBL inhibitors based on the DBO of avibactam, or other non-β-lactam cores, is of interest.
Perspectives
Take-home message (especially relevant to medics and medicinal chemists): It is not recommended to prescribe avibactam (branded as Avycaz, in combination with ceftazidime) for bacterial strains expressing metallo-β-lactamase-mediated resistance, as it is a weak binder and/or a poor substrate (with a hydrolysis mechanism different from that mediated by serine-β-lactamases). However, there is a scope for the development of dual inhibitors based on the diazabicyclooctane core of avibactam, which constitutes a major breakthrough in the field.
Martine I Abboud
University of Oxford
Read the Original
This page is a summary of: Interaction of Avibactam with Class B Metallo-β-Lactamases, Antimicrobial Agents and Chemotherapy, July 2016, ASM Journals,
DOI: 10.1128/aac.00897-16.
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