Global Analysis of the Co-Occurrence of Antimicrobial and Metal Resistance Genes in Bacterial Genomes From Dairy-Isolated Pathogens.

Metal contamination in dairy production can drive antimicrobial resistance co-selection independently of antibiotic use, yet the genomic architecture linking metal resistance and antimicrobial resistance across dairy-isolated pathogens remains largely uncharacterized globally. We analysed 3303 genomes from dairy environments across 52 countries, creating the first genome-resolved map of co-occurring resistance determinants in this critical agricultural interface. Metal/stress resistance genes were present at levels comparable to AMR genes (28.85% of isolates showed metal dominance), with arsenic (arsB: 42.6% prevalence) and copper/silver systems (silR: 98% in Klebsiella pneumoniae) frequently co-occurring with tetracycline (tet(38): 43%) and multidrug efflux determinants (lmrS: 43%). Statistical analysis of 29,299 gene pairs identified 523 significant associations (FDR < 0.05), revealing genetic linkage between arsenic resistance and tetracycline/multidrug efflux genes (Jaccard ≥ 0.98) in over 40% of isolates. Co-occurrence burden varied ninefold across taxa, with K. pneumoniae functioning as a super-reservoir species. Functional network analysis revealed that arsenic and copper resistance families operate as genomic hubs connecting to multiple antimicrobial classes, demonstrating that metal exposure maintains entire resistance modules through genetic linkage. These findings establish that AMR control strategies focused solely on antibiotic stewardship are insufficient; effective resistance mitigation requires integrated management of environmental metal contamination in dairy production systems.