The interplay between Mobilome and Resistome in Staphylococcus aureus

Abstract Antibiotic resistance genes (ARGs) in Staphylococcus aureus can disseminate vertically through successful clones, but also horizontally through the transfer of genes conveyed by mobile genetic elements (MGEs). The underexplored MGE/ARG associations in S . aureus favor the emergence of multidrug-resistant clones, posing a significant threat to human and animal health. This study investigated the interplay between the mobilome, encompassing MGEs, and the resistome, the collection of ARGs, in more than 10,000 S. aureus genomes from human and animal sources. The analysis revealed a remarkable diversity of MGEs and ARGs, with plasmids and transposons being the main carriers of resistance genes. Numerous MGE/ARG associations were identified, suggesting that MGEs play a critical role in the dissemination of resistance. A high degree of similaritywas observed in MGE/ARG associations between human and animal isolates, highlighting the potential for unrestricted spread of ARGs between hosts. While clonal expansion is a major driver of resistance dissemination in S. aureus , our results showed that MGEs and their associated ARGs can spread across different strain 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 the ir spread across several STs highlight the crucial role of MGEs in shaping the S. aureus resistome. Overall, this study provides valuable insights into the complex interplay between MGEs and ARGs in S. aureus , emphasizing the need to elucidate the mechanisms governing the epidemic success of MGEs, particularly those implicated in ARG transfer. Importance The research presented in this article highlights the crucial importance of understanding the interactions between mobile genetic elements (MGEs) and antibiotic resistance genes (ARGs) carried by Staphylococcus aureus , a versatile bacterium that can be both a harmless commensal and a dangerous pathogen for humans and animals. S. aureus strains represent a major threat due to their ability to rapidly acquire and disseminate ARGs. By analyzing a large dataset of S. aureus genomes, we highlighted the substantial role of MGEs, in particular plasmids and transposons, in the dissemination of ARGs within and between S. aureus populations, bypassing the host barrier. Given that multidrug-resistant S. aureus strains are classified as a high-prioritypathogenby global health organizations, this knowledge is crucial for understanding the complex dynamics of transmission of antibiotic resistance in this species.