Functional and structural analyses of amino acid sequence variation in PDC β-lactamase reveal different mechanistic pathways toward cefiderocol resistance in <i>Pseudomonas aeruginosa</i>.

ABSTRACT: A wide variety of clinically observed amino acid alterations in the Pseudomonas aeruginosa chromosomal β-lactamase AmpC (Pseudomonas-derived cephalosporinase [PDC]) are associated with increased resistance to cefepime, ceftolozane/tazobactam, or ceftazidime/avibactam, but their impact on cefiderocol resistance is unclear. We took advantage of a previously engineered collection of wild-type (PAO1) and iron uptake-deficient (PAO ΔpiuC) P. aeruginosa isolates producing 19 distinct PDC variants with substitutions in key catalytic regions. While most variants had moderate effects on cefiderocol minimum inhibitory concentrations compared to PDC-1, the E219K (Ω-loop) and L293P (helix H10) variants significantly affected cefiderocol activity. Kinetic studies revealed th

SUBMITTER: Gonzalez-Pinto L 

PROVIDER: S-EPMC12217463 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature