Genetic basis of cefiderocol resistance in Acinetobacter baumannii : insights from functional genomics and clinical isolates

Abstract

Cefiderocol (CFDC) is one of the few remaining antibiotics with activity against carbapenem-resistant Acinetobacter baumannii (CRAB), an urgent global health threat. Yet, resistance to CFDC is increasingly reported, and the underlying mechanisms remain incompletely defined. Most prior studies have examined single pathways, such as loss of TonB-dependent receptors. Here, we used genome-wide transposon mutagenesis together with genomic and phenotypic analysis of CFDC-resistant clinical isolates to generate a more comprehensive view of how resistance emerges. Our findings show that CFDC resistance is multifactorial, involving disrupted siderophore uptake, alterations in oxidative and envelope-stress responses, porin and cell-wall changes, and β-lactamase activity. By defining how these pathways converge, this work provides a broader mechanistic framework for interpreting emerging resistance in clinical settings. These insights underscore the need for integrated surveillance strategies and highlight the biological complexity that must be considered to preserve the effectiveness of this last-line antibiotic.