Genomic epidemiology of antimicrobial resistance in Proteus mirabilis: core genome and plasmid-mediated drivers.

Proteus mirabilis has emerged as a clinically significant multidrug-resistant (MDR) pathogen, yet the genomic drivers and dissemination mechanisms of its antimicrobial resistance (AMR) remain poorly characterized. To address this gap, we conducted a pangenome analysis of 2,013 P. mirabilis genomes, including 1,990 publicly available strains and 23 newly sequenced clinical isolates, to delineate the species-wide AMR landscape. Our study identified 197 AMR gene subtypes spanning 12 antibiotic classes, with seven resistance determinants embedded in the core genome. Clinically critical resistance phenotypes-notably to third-generation cephalosporins and carbapenems-were strongly associated with the proliferation of β-lactamase genes (blaTEM-1, blaCTX-M-15, blaNDM-1) across lineages. Strikingly, 36.4% of AMR genes resided on mobile genetic elements, with conjugative IncC plasmids acting as primary vectors for high-risk resistance cassettes, including β-lactamase (blaTEM-1, blaNDM-1) and aminoglycoside-modifying [aac(6')-Ib-cr, aph(3'')-Ib] genes. Phylogenetic reconstruction revealed that blaNDM-1-carrying IncC plasmids formed interspecies clusters with homologs from Klebsiella pneumoniae, Escherichia coli, and Salmonella enterica, demonstrating active cross-genera transmission within Enterobacteriaceae. These findings highlight two parallel evolutionary strategies in P. mirabilis: the conservation of core genome resistance mechanisms and horizontal acquisition of plasmid-borne MDR traits, which provide comprehensive understanding of AMR transmission in the bacterium.