Biochemical Insights into Imipenem Collateral Susceptibility Driven by ampC Mutations Conferring Ceftolozane/Tazobactam Resistance in Pseudomonas aeruginosa

Abstract

Several Pseudomonas aeruginosa AmpC mutants have emerged that exhibit enhanced activity against ceftazidime and ceftolozane, while also evading inhibition by avibactam. Interestingly, P. aeruginosa strains harboring these AmpC mutations fortuitously exhibit enhanced carbapenem susceptibility. This acquired susceptibility was investigated by comparing the degradation of imipenem by wild-type and cephalosporin-resistant AmpC. We show that cephalosporin-resistant AmpC enzymes lose their efficacy for hydrolyzing imipenem and suggest that this may be due to their increased flexibility and dynamics relative to the wild type.

Keywords: AmpC; Pseudomonas aeruginosa; antibiotic resistance; beta-lactamase; imipenem.

FIG 1

Active site structures of AmpC with ceftazidime (PDB accession number 1IEL) (A) and imipenem (1LL5) (B). Residues are labeled with numbers corresponding to E. coli AmpC; numbers in parentheses correspond to Pseudomonas aeruginosa PAO1. α-Helix residues (91 to 106) is shown in yellow, α-helix residues (154 to 165) appears in green, and Ω-loop residues (229 to 247) is indicated in magenta.