Atomic-Resolution Structure of a Class C β-Lactamase and Its Complex with Avibactam

Area of Science:

• Biochemistry
• Structural Biology
• Microbiology

Background:

• Beta-lactamases (BLs) confer antibiotic resistance, reducing the effectiveness of beta-lactam drugs.
• Avibactam is a pioneering non-beta-lactam BL inhibitor used in combination therapies.
• Ceftazidime-avibactam is a critical antibiotic for treating infections caused by highly resistant bacteria.

Purpose of the Study:

• To elucidate the structural basis of avibactam inhibition using the TRU-1 beta-lactamase as a model.
• To compare the binding of avibactam to TRU-1 and Pseudomonas aeruginosa AmpC.
• To gain insights into the mechanism of avibactam carbamylation and recyclization.

Main Methods:

• Ultrahigh-resolution X-ray crystallography of native TRU-1 and its complex with avibactam.
• Comparative structural analysis of TRU-1 and Pseudomonas aeruginosa AmpC in complex with avibactam.
• Analysis of residue conformations involved in substrate and inhibitor binding.

Main Results:

• Detailed structural information on the native TRU-1 enzyme and its complex with avibactam.
• Identification of conformational changes in residues critical for binding.
• Observation of two distinct avibactam conformations in TRU-1 and P. aeruginosa AmpC, suggesting different mechanistic states.

Conclusions:

• The study provides high-resolution structural insights into avibactam's interaction with a class C beta-lactamase.
• Understanding these interactions can inform the development of new inhibitors to combat antibiotic resistance.
• The findings highlight the dynamic nature of inhibitor binding and mechanism.