Abstract
Invasive non-typhoidal Salmonella (iNTS) disease, primarily manifesting as bloodstream infections and dominated by Salmonella Typhimurium sequence type 313 (ST313), represents a major global health challenge, particularly in sub-Saharan Africa. However, the transmission landscape and evolutionary driver of ST313 remain incompletely understood. Here, we compile the global dataset to date, comprising 11,361 human-derived iNTS genomes and 3115 ST313 genomes from diverse sources, enabling identification of a highly antimicrobial-resistant sublineage 2.4 and an emerging lineage 4. Phylogenomic analyses reveal patterns consistent with intercontinental dissemination of ST313, which may be associated with modernized human biomass movement. Sublineage 2.4, an antimicrobial-resistant offshoot that displaced lineage 1, harbors extended-spectrum β-lactamase genes, including bla(OXA-1), bla(CTX-M-15), often linked to mobilome, suggesting a potential trend of increasing resistance within lineage 2. Furthermore, mobilome-driven alterations in antimicrobial-resistant gene carriage coincide with the post-2006 decline of lineage 1 in Africa. Additional genetic changes may enhance invasiveness and competitive fitness , including enrichment of pseudogenes and positively selected functional genes, which may have facilitated replacement by newly identified ST313 clone. Together, Our findings highlight lineage-specific selection pressures shaped by anthropogenic factors, such as antimicrobial use and stewardship, that modulate ST313 evolution and underscore the need for enhanced surveillance.