Ecological functions coupled with plasmid and phage-mediated dissemination drive the global prevalence of high-risk antimicrobial resistance genes in influent

Antibiotic resistance genes (ARGs) in wastewater treatment plant (WWTP) influent pose potential global risk to public health. However, the spatiotemporal distribution of global influent ARGs, the highly prevalent core ARGs components, and their transmission mechanisms remain unclear. The resistance risk ranking integrating abundance, mobility, and pathogenicity in actual influent samples is still undefined. Here, we conducted a global analysis of influent samples from six continents, identifying 392 ARGs, including 20 items from the WHO priority list. The abundance and diversity of ARGs exhibited continent-specific patterns, with their composition across countries influenced by economic status and population size. Temporal analysis revealed interannual shifts in ARGs community structure with composition similarity declining significantly over time (Bray-Curtis dissimilarity > 0.3 after 300 days). We identified 37 core ARGs (prevalence > 50 %) that reflected overall resistance profiles, including high-risk cases like vanS, lsaE, and tetM that were frequently co-located with mobile genetic elements (MGEs). The core ARGs were often genetically linked to sulfur and nitrogen cycling functions and densely associated with MGEs, suggesting metabolic-related environmental selection may facilitate their high prevalence. Less-developed countries are more likely to exhibit a greater diversity of high-risk-ranked ARGs. The co-localization of plasmids and phages with ARGs is a major driver of high-risk ARGs dissemination. Our findings provide potential mechanisms for the transmission of ARGs and critical insights into previously unrecognized high-risk ARGs for global wastewater surveillance and risk prioritization.