Dominique Snel

Introduction
Cefiderocol is a siderophore cephalosporin with potent activity against multidrug-resistant Gram-negative bacteria, including Acinetobacter baumannii. This study investigated which genomic changes arise in A. baumannii when it is repeatedly exposed to cefiderocol.

Methods
A. baumannii ATCC 19606 was serially passaged in cation adjusted Mueller–Hinton broth with increasing cefiderocol concentrations. Minimum Inhibitory Concentrations (MICs) were determined using the UMIC® Cefiderocol system. Whole genome sequencing was performed on GridION (Oxford Nanopore) after library preparation with SQK RBK.14.23, followed by assembly (Flye), quality control (Quality Assessment Tool (QUAST), Bandage), annotation (Bakta), resistance gene profiling (Center of genomic epidemiology (CGE)), and variant calling in CLC Genomics Workbench.

Results
The parental strain carried only intrinsic resistance genes (blaOXA 51 like, catB7, aph(3’)-IIb) and no known cefiderocol resistance determinants. After four passages, the cefiderocol MIC rose 16 fold from 0.125 to 2 mg/L. Sequencing of passage 2–5 isolates identified a novel 105 nt deletion in fiu, encoding a TonB dependent iron–catecholate receptor, likely producing a truncated, non functional Fiu transporter and reducing cefiderocol uptake. Additional variants in stress response and cell surface genes suggested compensatory adaptation during drug exposure.

Conclusion
Repeated cefiderocol exposure drove rapid adaptation in A. baumannii, centered on a loss of function mutation in the TonB dependent Fiu transporter. These findings implicate iron uptake pathways in cefiderocol resistance and emphasize the capacity of A. baumannii to remodel its surface and transport systems under antibiotic pressure, supporting further work on Fiu mediated resistance and surveillance for similar mutations.