Essential role of the leucine-293 for the AmpC β-lactamase in the resistance to cefepime, cefiderocol, and new β-lactams/β-lactamase inhibitor combinations in Enterobacter hormaechei.

OBJECTIVES

Cefepime (FEP) is used to treat Enterobacter spp. infections, yet resistance mechanisms remain incompletely defined. This study aimed to characterize the emergence of this broad-spectrum resistance phenotype in an AmpC-hyperproducing, FEP-susceptible E. hormaechei isolate exposed to FEP.

METHODS

We exposed an AmpC-hyperproducing, FEP-susceptible Enterobacter hormaechei isolate to escalating cefepime concentrations and selected a mutant with high-level resistance to FEP, FEP/β-lactamase inhibitor combinations, ceftazidime/avibactam and cefiderocol. Whole-genome sequencing, AmpC Escherichia coli cloning, and structure-based modelling were performed to define the underlying resistance mechanism.

RESULT: The selected mutant harboured a single Leu293 deletion in AmpC, which was sufficient to generate this broad-spectrum resistance.

CONCLUSIONS

These findings define Leu293 as a key AmpC mutational hotspot with implications for clinical microbiology.