Interaction of Avibactam with Class B Metallo-β-Lactamases

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• β-Lactamases are key mechanisms of resistance to β-lactam antibiotics.
• Serine β-lactamases (SBLs) and metallo-β-lactamases (MBLs) are the two main classes.
• Avibactam is a non-β-lactam inhibitor targeting SBLs, often used with ceftazidime.

Purpose of the Study:

• To investigate the biochemical and biophysical interactions of avibactam with metallo-β-lactamases (MBLs).
• To assess avibactam's efficacy against MBL-mediated resistance across all three MBL subfamilies (B1, B2, B3).

Main Methods:

• Biochemical assays to study binding and reactivity.
• Biophysical techniques to analyze interactions.
• Testing avibactam against representative MBLs from subfamilies B1, B2, and B3.

Main Results:

• Avibactam demonstrates limited or no activity against MBL-mediated resistance.
• Avibactam does not inhibit MBLs and exhibits weak binding to most tested MBLs.
• Avibactam undergoes slow hydrolysis and CO2 loss with some MBLs, a process distinct from SBL interactions.

Conclusions:

• Avibactam is not an effective inhibitor of metallo-β-lactamases.
• The development of MBLs capable of hydrolyzing avibactam is a potential future concern.
• Designing dual-action inhibitors targeting both SBLs and MBLs, potentially using the avibactam scaffold, could be a productive strategy.