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Life sciences · Journal article
Microbiology Spectrum · October 23, 2026
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ABSTRACT Streptococcus equi subsp. zooepidemicus ( S. zooepidemicus ) is a zoonotic pathogen affecting various mammals, yet its genomic epidemiology remains poorly understood. To address this, we analyzed 428 S. zooepidemicus strains from six countries (1993–2024). The whole-genome single-nucleotide polymorphism (SNP) revealed four clades, with genetic diversity driven by lineage rather than host species or geographic origin. The findings support the conclusion that S. zooepidemicus is a host generalist, with horses serving as the primary host. The identified virulence-associated genes (VAGs) showed clade-specific distribution patterns: clade 1 lacked adherence factor genes srtC.2/3/4, clade 2 was enriched for the IgG-degrading enzyme gene ideZ, and clade 4 was enriched for a specific allele of the virulence-associated coupling protein gene virD4. Antimicrobial resistance genes (ARGs) were detected in 18.2% of strains, and no multidrug resistance was found. ARG prevalence was associated with clade 4, with tetracycline resistance being the most common. Mobile genetic elements (MGEs) are pivotal in shaping the accessory genome profiles: prophages function as the primary carriers of exotoxin genes, while integrative and conjugative elements (ICEs) serve as the main vehicles for ARGs. Notably, the co-localization of the invasion-associated virD4 allele and ARGs was identified on ICE Sz 1, predominantly in clade 4 isolates. In conclusion, the pathogenic potential and resistance profiles of S. zooepidemicus are shaped by specific evolutionary lineages driven by MGEs. These elements act not only as genetic cargo but also as drivers that provide the conjugative machinery to co-disseminate virulence and resistance traits, accelerating the evolution of zoonotic lineages. IMPORTANCE S. zooepidemicus is an opportunistic pathogen capable of infecting a wide range of hosts, including humans, often causing severe diseases. This study provides a framework for understanding the evolution of S. zooepidemicus, highlighting that its pathogenic potential and antimicrobial resistance (AMR) profiles are shaped by specific MGE-driven evolutionary lineages. The co-localization of the invasion-associated virD4 allele and ARGs on ICEs indicates that these elements provide both the pathogenic advantage and the conjugative machinery required for horizontal spread in S. zooepidemicus. This suggests that antibiotic selection can promote the transmission of virulent S. zooepidemicus lineages. These findings underscore the need for integrated surveillance strategies to monitor both virulence and AMR traits in S. zooepidemicus within equine populations to benefit public health.