Insights into the activity of cefiderocol against PER-2 producing Enterobacterales

Abstract

The PER-2 β-lactamase is a unique class A enzyme conferring broad spectrum cephalosporin resistance. In this study, we explored the stability of cefiderocolcefiderocolcefiderocol(FDC) against PER-2 β-lactamase to gain insights into structure activity relationships (SAR) of this synthetic siderophore-conjugated antibiotic. Herein, we show that the MICs of FDC for PER-2 producing isolates and transformants ranged between 0.125 and 64 μg/mL; diazabicyclooctanes (DBOs) reduced the MIC values. In PER-2 mutants, MIC values decreased up to 10–12 dilutions in agreement with previous observations especially in the case of Arg220 substitutions. Catalytic efficiency for PER-2 was 0.072 μM−1 s−1, comparable with PER-1 (0.046 μM−1 s−1) and NDM-1 (0.067 μM−1 s−1). In silico models revealed that FDC within the active site of PER-2 demonstrates unique interactions as a result of the inverted Ω loop fold and extension of the β3-β4 connecting loop.