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

Gabriel Cabot ¹, Kihun Kim ², Brian L. Mark ², Antonio Oliver¹, Mazdak Khajehpour ³

¹Research Unit, University Hospital Son Espases – Health Research Institute of the Balearic Islands (IdISBa), Palma, Spain.

²Department of Microbiology, University of Manitoba, Winnipeg, Canada.

³Department of Chemistry, University of Manitoba, Winnipeg, Canada.

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.

Antimicrob Agents and Chemoter. 2023 Feb 16; 67(2):e0140922. doi: 10.1128/aac.01409-22.

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