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Interactions between Avibactam and Ceftazidime-Hydrolyzing Class D β-Lactamases.
Jean-Marie Frère1, Pierre Bogaerts2, Te-Din Huang2
1Centre for Protein Engineering, University of Liège, B 4000 Liège, Belgium.
Biomolecules
|March 27, 2020
Summary
Class D beta-lactamases show varied activity against beta-lactam antibiotics. Certain ceftazidime-hydrolyzing OXA enzymes are more sensitive to avibactam, offering clinical potential for combination therapy.
Area of Science:
- Microbiology
- Enzymology
- Pharmacology
Background:
- Class D beta-lactamases (OXA enzymes) display diverse hydrolysis profiles against clinically relevant beta-lactams.
- Their susceptibility to avibactam inactivation varies significantly, impacting treatment efficacy.
- Understanding these variations is crucial for developing effective antimicrobial strategies.
Purpose of the Study:
- To kinetically characterize the interaction between two ceftazidime-hydrolyzing OXA enzymes and avibactam.
- To compare the susceptibility of these enzymes to avibactam inactivation relative to other Class D beta-lactamases.
- To assess the clinical implications of these findings for avibactam-ceftazidime combination therapy.
Main Methods:
- Detailed kinetic analysis of enzyme-inhibitor interactions.
- Enzyme assays measuring hydrolysis rates.
- Comparative susceptibility testing against avibactam.
Main Results:
- Two ceftazidime-hydrolyzing OXA enzymes demonstrated significantly higher susceptibility to avibactam.
- These enzymes were more readily inactivated by avibactam compared to other Class D beta-lactamases lacking ceftazidime hydrolysis.
- A notable difference in inactivation rates was observed, exceeding a factor of 100 for some enzymes.
Conclusions:
- Ceftazidime-hydrolyzing OXA enzymes are particularly vulnerable to avibactam.
- This heightened susceptibility supports the clinical use of avibactam in combination with ceftazidime for treating infections caused by these resistant bacteria.
- The findings highlight enzyme-specific interactions influencing the effectiveness of beta-lactamase inhibitors.
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