Structural insight into potent broad-spectrum inhibition with reversible recyclization mechanism: avibactam in complex with CTX-M-15 and Pseudomonas aeruginosa AmpC β-lactamases

Antimicrob Agents Chemother. 2013 Jun;57(6):2496-505. doi: 10.1128/AAC.02247-12. Epub 2013 Feb 25.

Abstract

Although β-lactams have been the most effective class of antibacterial agents used in clinical practice for the past half century, their effectiveness on Gram-negative bacteria has been eroded due to the emergence and spread of β-lactamase enzymes that are not affected by currently marketed β-lactam/β-lactamase inhibitor combinations. Avibactam is a novel, covalent, non-β-lactam β-lactamase inhibitor presently in clinical development in combination with either ceftaroline or ceftazidime. In vitro studies show that avibactam may restore the broad-spectrum activity of cephalosporins against class A, class C, and some class D β-lactamases. Here we describe the structures of two clinically important β-lactamase enzymes bound to avibactam, the class A CTX-M-15 extended-spectrum β-lactamase and the class C Pseudomonas aeruginosa AmpC β-lactamase, which together provide insight into the binding modes for the respective enzyme classes. The structures reveal similar binding modes in both enzymes and thus provide a rationale for the broad-spectrum inhibitory activity of avibactam. Identification of the key residues surrounding the binding pocket allows for a better understanding of the potency of this scaffold. Finally, avibactam has recently been shown to be a reversible inhibitor, and the structures provide insights into the mechanism of avibactam recyclization. Analysis of the ultra-high-resolution CTX-M-15 structure suggests how the deacylation mechanism favors recyclization over hydrolysis.

MeSH terms

  • Acylation
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / metabolism
  • Azabicyclo Compounds / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Crystallization
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / enzymology
  • Structure-Activity Relationship
  • X-Ray Diffraction
  • beta-Lactamase Inhibitors*
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism
  • beta-Lactams / chemistry
  • beta-Lactams / metabolism
  • beta-Lactams / pharmacology

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Bacterial Proteins
  • beta-Lactamase Inhibitors
  • beta-Lactams
  • avibactam
  • beta-lactamase CTX-M-15
  • AmpC beta-lactamases
  • beta-Lactamases

Associated data

  • PDB/4GZB
  • PDB/4HBT
  • PDB/4HBU
  • PDB/4HEF