Genomic analysis reveals multi-level resistance network linking oxidative stress pathway mutations to cefiderocol resistance and clonal evolution in

Introduction: Resistance to cefiderocol (CFDC), a novel siderophore-cephalosporin, remains poorly understood. We aimed to explore mutations in oxidative stress (OS) pathways in Methods: A total of 282 KPN strains from the United Arab Emirates were tested for susceptibility to various antibiotics, including CFDC. Afterward, 96 representative strains were subjected to whole-genome sequencing and bioinformatic analyses to examine 51 genes across six functional categories (OxyR, SoxRS, iron regulation, efflux pumps, DNA repair, and penicillin-binding proteins). Genotypic and phenotypic results were correlated to explore significant associations with CFDC susceptibility. Results: CFDC demonstrated high Conclusions: Coordinated interactions across iron regulation, OS, and efflux pathways are associated with reduced susceptibility to CFDC. The negative correlation between OxyR/DNA repair mutations and CFDC MICs suggests that intact OS defenses paradoxically reduce CFDC efficacy. OS pathway integrity may modulate CFDC susceptibility, informing future strategies to preserve CFDC efficacy. The identification of specific mutations linked to CFDC resistance provides potential biomarkers for surveillance and therapeutic targeting, underscoring the interplay between OS responses and antimicrobial resistance.