Experimental evolution of cefiderocol resistance in Pseudomonas aeruginosa

• Published in: Heliyon
• Main Authors: Igor Chebotar, Konstantin Kuleshov, Julia Bocharova, Nikolay Mayanskiy
• Format: Article
• Language: English
• Published: Elsevier 2025-08-01
• Subjects: Pseudomonas aeruginosa; Antibiotic resistance; Cefiderocol; Mutation
• Online Access: http://www.sciencedirect.com/science/article/pii/S2405844025020675

Cefiderocol is a novel and promising cephalosporin approved for treating severe infections caused by Gram-negative bacteria with limited therapeutic options. One of the primary targets of cefiderocol is Pseudomonas aeruginosa, a significant opportunistic Gram-negative pathogen. In this study, we utilized a spatiotemporal evolution model to investigate the molecular mechanisms of cefiderocol resistance in the P. aeruginosa ATCC 27833 reference strain (Pa_ATCC) grown over an increasing 5-step cefiderocol concentration gradient from 0 to 30 mg/L. Within 11 days, the experimental strain achieved the maximum cefiderocol concentration band of 30 mg/L. Isolates of Pa_ATCC collected at different time points and across varying cefiderocol concentration bands exhibited increases in minimum inhibitory concentrations (MICs) up to 4–32-fold higher compared to baseline levels. To identify genomic alterations occurring during cefiderocol adaptation, 45 collected isolates were subjected to whole genome sequencing. In total, 12 unique sequence alteration variants in eight genes and three intergenic mutations were detected; however, one major clone with the highest MIC elevations, which emerged around day 10 of the experiment within the 10 mg/L cefiderocol band, harbored alterations in pchR, pirR, rpoD, and rppH in conjunction with two intergenic mutations. Additional mutations were scattered among other isolates but were not conserved. Thus, our experimental model elucidated a distinctive combination of genetic changes driving the emergence of cefiderocol resistance in P. aeruginosa.