Comprehensive genomic analysis of antibiotic resistance plasmids in animal-associated Staphylococcus aureus in France

ABSTRACT In Staphylococcus aureus , an animal pathogen and zoonotic agent, plasmids play a pivotal role in the acquisition and spread of antibiotic resistance genes (ARGs). This study investigated the plasmid content of 329 S . aureus isolates from livestock and companion animals collected in France between 2010 and 2021. Plasmids ( n = 211) were identified from 139 isolates. The major families identified— rep7a , rep20 , and rep10 —were associated with specific resistance genes ( str , cat , blaZ , erm (C)) and exhibited widespread horizontal transfer across different S. aureus sequence types (STs) and animal hosts. In temporal analysis, the rep7a /str and rep7a / cat plasmids circulating in horses were progressively replaced by a rep7a plasmid carrying both str and cat genes. The study also highlighted the presence of mosaic plasmids, which combined elements from different bacterial species/genera, confirming the broad host range of S. aureus plasmids and their ability to acquire ARGs from diverse sources. Moreover, the occurrence of hybrid plasmids (carrying multiple rep genes) underscores the plasticity of these vectors of ARGs. This study emphasizes the need to investigate the mechanisms driving the spread and persistence of antibiotic-resistant plasmids in S. aureus , with a view to developing strategies aimed at combating antibiotic resistance. IMPORTANCE The spread of antibiotic resistance in Staphylococcus aureus is a growing concern, particularly in animals that can serve as reservoirs for resistant strains. This study highlights the crucial role of plasmids in transmitting resistance genes among different animal hosts and S. aureus lineages. The characterization of 329 isolates collected over 10 years revealed how certain plasmid families are associated with specific resistance genes and how they evolve over time. The occurrence of mosaic and hybrid plasmids further underscores the ability of S. aureus to acquire resistance from diverse bacterial sources. These findings provide key insights into the mechanisms shaping antibiotic resistance in this pathogen and emphasize the fact that understanding plasmid-driven resistance is essential for developing effective interventions to limit the spread of multidrug-resistant S. aureus in both veterinary and human medicine.