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

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 12 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 clinical wild-type or TEM-producing E. coli (WT/TEM-Ec) and NDM-producing (NDM-Ec) isolates. The distribution of iron uptake genes was assessed in these isolates. In addition, fec operon prevalence and genomic location were investigated in E. coli genomes from EnteroBase and RefSeq databases. Among Keio and 536-PAI-deleted mutants, only {Delta}cirA and {Delta}fiu (enterobactin system) showed increased FDC MICs (8- and 3-fold, respectively), while {Delta}fecA and {Delta}fecB 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 in those with MICs below (94% vs. 38% in WT/TEM-Ec; 100% vs. 0% in NDM-Ec). According to EUCAST breakpoints, 66.7% of fec-positive NDM-Ec were resistant to FDC while 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, 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.