The interplay between mobilome and resistome in <i>Staphylococcus aureus</i>

Antibiotic resistance genes (ARGs) in <i>Staphylococcus aureus</i> can disseminate vertically through successful clones, but also horizontally through the transfer of genes conveyed by mobile genetic elements (MGEs). Even though underexplored, MGE/ARG associations in <i>S. aureus</i> favor the emergence of multidrug-resistant clones, which are challenging therapeutic success in both human and animal health. This study investigated the interplay between the mobilome and the resistome of more than 10,000 <i>S</i>. <i>aureus</i> genomes from human and animal origin. The analysis revealed a remarkable diversity of MGEs and ARGs, with plasmids and transposons being the main carriers of ARGs. Numerous MGE/ARG associations were identified, suggesting that MGEs play a critical role in the dissemination of resistance. A high degree of similarity was observed in MGE/ARG associations between human and animal isolates, highlighting the potential for unrestricted spread of ARGs between hosts. Our results showed that in parallel to clonal expansion, MGEs and their associated ARGs can spread across different strain types sequence types (STs), favoring the evolution of these clones and their adaptation in selective environments. The high variability of MGE/ARG associations within individual STs and their spread across several STs highlight the crucial role of MGEs in shaping the <i>S. aureus</i> resistome. Overall, this study provides valuable insights into the complex interplay between MGEs and ARGs in <i>S. aureus</i>, emphasizing the need to elucidate the mechanisms governing the epidemic success of MGEs, particularly those implicated in ARG transfer.IMPORTANCEThe research presented in this article highlights the importance of understanding the interactions between mobile genetic elements (MGEs) and antibiotic resistance genes (ARGs) carried by <i>Staphylococcus aureus</i>, a versatile bacterium that can be both a harmless commensal and a dangerous pathogen for humans and animals. <i>S. aureus</i> has a great capacity to acquire and disseminate ARGs, enabling efficient adaption to various environmental or clinical conditions. By analyzing a large data set of <i>S. aureus</i> genomes, we highlighted the substantial role of MGEs, particularly plasmids and transposons, in disseminating ARGs within and between <i>S. aureus</i> populations, bypassing host barriers. Given that multidrug-resistant <i>S. aureus</i> strains are classified as a high-priority pathogen by global health organizations, this knowledge is crucial for understanding the complex dynamics of transmission of antibiotic resistance in this species.