Integrating serotyping, MLST, and phenotypic data: decoding the evolutionary drivers of <i>Salmonella</i> pathogenicity and drug resistance

Global surveillance of <i>Salmonella enterica</i> reveals dynamic evolutionary forces shaping pathogenicity and antimicrobial resistance (AMR), yet the integration of serotyping, multilocus sequence typing (MLST), and phenotypic landscapes remains unexplored. Here, we dissect 935 <i>Salmonella</i> isolates, collected from both clinical and food chain sources, through integrated genomics and phenomics to resolve population structure, spatiotemporal dynamics, and evolutionary drivers. <i>Salmonella Typhimurium</i> (18.7%) and <i>Salmonella Enteritidis</i> (17.1%) dominate the serotype landscape, while MLST uncovers ST34 (20.7%) as the pivotal sequence type bridging multiple serotypes. Temporal tracking (2018-2022) exposes alarming AMR trajectories: ciprofloxacin resistance doubled (15.3% to 30.4%) by 2020, and tetracycline resistance peaked at 77.3%. The serotype-specific epidemiology reveals that <i>S. Typhimurium</i> declined and then stabilized, <i>S. Enteritidis</i> fluctuated due to vaccination, and <i>S. Derby</i> emerged persistently (+69%). Network analysis reveals two evolutionary clusters: one anchored by <i>S. Typhimurium/S. Enteritidis</i>-ST34/ST11 and another harboring diverse STs associated with <i>S. Derby</i>. Notably, ST34 acts as a genetic backbone for serotype switching. Notably, <i>S. Typhimurium</i> exhibits the highest AMR gene burden (median: 4.2 genes/isolate) and virulence arsenal (<i>spvB</i>: 85.1%; <i>pefA</i>: 75.4%), which correlates with invasive disease. Geographic heterogeneity results in distinct serotype distributions: <i>S. Enteritidis</i> dominates in Xinyu (28.4%), <i>S. Typhimurium</i> prevails in Shangrao (31.5%), and Ganzhou exhibits balanced diversity. Our findings establish that clonal expansion, horizontal gene transfer, and regional ecologies are key factors jointly driving <i>Salmonella</i> evolution. This necessitates genotype-phenotype-integrated surveillance to preempt the emergence and widespread dissemination of resistance and virulence.IMPORTANCE<i>Salmonella enterica</i> is a globally significant foodborne pathogen, whose pathogenicity and antimicrobial resistance (AMR) evolution are driven by complex mechanisms. This study provides a comprehensive analysis of 935 <i>Salmonella</i> isolates from clinical and food chain sources, integrating genomic and phenotypic data to elucidate population structure, spatiotemporal dynamics, and key evolutionary drivers. We reveal critical resistance trends, including a concerning doubling of ciprofloxacin resistance by 2020 and sustained high tetracycline resistance. Our comparative analysis of serotypes (e.g., <i>S. Typhimurium</i> and <i>S. Enteritidis</i>) highlights associations between AMR gene burden and virulence factors and identifies ST34 as a pivotal genetic element facilitating serotype switching. These findings underscore the imperative for integrated genotypic-phenotypic surveillance to predict resistance evolution and inform "One Health"-based interventions. By disrupting AMR dissemination across the animal food chain, this research offers novel strategies for global <i>Salmonella</i> control and improved public health outcomes.