Resistance architectures underpin the evolution of antimicrobial resistance in Acinetobacter baumannii

Abstract Carbapenem-resistant Acinetobacter baumannii (CRAB) is a critical-priority hospital pathogen for which genome-based surveillance increasingly informs antimicrobial resistance (AMR) detection. However, AMR-gene carriage alone does not explain the magnitude of carbapenem resistance (CR) or the evolutionary success of the lineages carrying these genes. We analysed a 16-year clinical isolate collection within a global genomic framework to investigate how CR emerges, persists and spreads. Despite widespread carbapenemase carriage, carbapenem MICs varied markedly. We identified two recurrent Resistance Architectures: genomic configurations comprising distinct AMR genes, mobile genetic elements, associated genomic features and lineage backgrounds that converged on similar CR phenotypes. A globally disseminated IC2-associated bla OXA−23 architecture contrasted with a regionally enriched IC6-associated plasmid-borne bla OXA−72 architecture, yet both were associated with high-level CR. Our findings suggest that clinically successful carbapenem-resistant emerges through the assembly of compatible genomic architectures rather than AMR-gene acquisition alone, providing a framework for interpreting AMR evolution and improving genome-based surveillance.