Influence of iron uptake systems on cefiderocol activity in Escherichia coli: At the crossroads of antibiotic resistance and virulence

Abstract

ABSTRACT Cefiderocol (FDC) is a new siderophore-conjugated cephalosporin that enters the periplasm via iron transport systems. However, the specific contribution of individual iron uptake pathways to FDC activity remains unclear. We investigated the role of 13 iron acquisition systems using several Escherichia coli strain collections. FDC MICs were determined in iron-depleted and iron-supplemented media for E. coli mutants (Keio and pathogenic island [PAI]-deleted collections) and for no-acquired β-lactamase or TEM (NoBL/TEM-Ec) and NDM-producing E. coli (NDM-Ec) clinical isolates. Prevalence of iron uptake genes was assessed in these isolates, and fec operon prevalence and genomic location were investigated in E. coli genomes from EnteroBase and RefSeq databases. Compared to K-12 and 536 reference E. coli, only ΔcirA and Δfiu (enterobactin system) showed increased FDC MICs (8- and 3-fold, respectively), while ΔfecA and ΔfecB had lower MICs (3-fold decrease). The fec operon, a known extraintestinal virulence factor, was significantly more prevalent in isolates with FDC MICs above median than below (96% vs. 33% in NoBL/TEM-Ec; 100% vs. 0% in NDM-Ec). According to EUCAST breakpoints, 63.6% of fec-positive NDM-Ec were resistant to FDC, whereas none of the fec-negative were. The fec operon was found in 46.5% of E. coli genomes, including virulent clones (ST131, 77%) and was mostly chromosome-borne (99%). Plasmid-borne fec closely resembled that of Enterobacter hormaechei or Klebsiella pneumoniae, suggesting interspecies transfer. Our findings highlight the role of Fec in reducing FDC susceptibility and promoting resistance in NDM-producing E. coli. They challenge the virulence-resistance trade-off demonstrating the “liaisons dangereuses” between iron and antibiotics.