Genomic epidemiology and lineage‐specific risk stratification of tet (X4)‐mediated tigecycline resistance along the pork production chain: A One Health perspective

ABSTRACT Tigecycline serves as a last‐resort antibiotic, yet its efficacy is increasingly compromised by the rapid dissemination of the plasmid‐borne resistance gene tet (X4). While metagenomics has broadened our understanding of resistomes, high‐resolution genomic tracking of resistant clones across the entire farm‐to‐table continuum remains critical. In this study, we conducted a large‐scale surveillance project in China, analyzing 2216 samples across the pork production chain and isolating 1288 tigecycline‐resistant strains. Our genomic analysis revealed a distinct transmission dynamic: while intensive pig farms exhibited the highest recovery rate under selective enrichment, slaughterhouses acted as a critical enrichment node and served as a reservoir and potential source for the introduction of resistant strains into downstream food systems. Notably, occupational exposure emerged as an important exposure pattern, with pig farm workers showing markedly higher carriage rates than the general population. Whole‐genome sequencing of 790 tet (X4)‐positive Escherichia coli isolates revealed a population structure dominated by phylogroups A and B1. ST10 and ST195 were the most prevalent lineages and showed extensive putative clonal relatedness across the farm‐slaughterhouse interface. We identified 2574 putative clonal relatedness events (SNPs ≤ 10), heavily concentrated in the farm‐slaughterhouse interface. To assess public health threats, we developed a lineage‐specific risk stratification model by integrating global datasets. This revealed two parallel risk trajectories: the enrichment of multidrug‐resistant commensals in processing nodes and the convergence of hyper‐virulence and resistance in specific Hybrid lineages. Furthermore, analysis of 234 tet (X4)‐bearing plasmids elucidated a conserved IS Vsa3 ‐ rdmC ‐ tet (X4) genetic module carried primarily by IncF/IncHI/IncX1 backbones. We further uncovered that the stability of these plasmids is underpinned by lineage‐specific Toxin‐Antitoxin systems, specifically the double‐lock mechanism (RelBE and Phd/Doc) in dominant IncX1 plasmids. These findings highlight farms and slaughterhouses as pivotal control points and demonstrate the power of integrated genomic surveillance in guiding One Health strategies to mitigate the spread of tet (X4).