Objectives Staphylococcus aureus is a leading cause of hospital acquired infections worldwide. Over recent decades, methicillin resistant Staphylococcus aureus (MRSA), which is resistant to multiple antimicrobials, has emerged as a significant pathogenic strain in both hospital and community settings. The rapid emergence and dissemination of MRSA clones are driven by a dynamic and evolving population, spreading swiftly across regions on epidemiological time scales. Despite the vast geographical expanse and diverse demographics of the Kingdom of Saudi Arabia and the broader West Asia region, the population diversity of MRSA in hospitals in these areas remains underexplored. Methods We conducted a large scale genomic analysis of a systematic Staphylococcus aureus collection obtained from 34 hospitals across all provinces of KSA, from diverse infection sites between 2022 and 2024. The dataset comprised 582 MRSA and 30 methicillin susceptible Staphylococcus aureus (MSSA) isolates, all subjected to whole genome sequencing. A combination of phylogenetic and population genomics approaches was utilized to analyze the genomic data. A hybrid sequencing approach was employed to retrieve the complete plasmid content. Results The population displayed remarkable diversity, comprising 35 distinct sequence types (STs), with the majority harboring community associated SCCmec loci (types IVa, V VII, and VI). Virulence factors associated with community acquired MRSA (CA MRSA), including Panton Valentine Leukocidin (PVL) genes, were identified in 12 distinct STs. Dominant clones, including ST8 t008 (USA300), ST88 t690, ST672 t3841, ST6 t304, and ST5 t311, were associated with infections at various body sites and were widely disseminated across the country. Linezolid and vancomycin resistance were mediated by cfr carrying plasmids and mutations in the vraR gene (involved in cell wall stress response) and the murF gene (peptidoglycan biosynthesis) in five isolates, respectively. Phylodynamic analysis revealed the rapid expansion of the dominant clones, with their emergence estimated to have occurred 10 20 years ago. Plasmidome analysis uncovered a diverse repertoire of blaZ containing plasmids and the sharing of erm(C) encoding plasmids among major clades. The acquisition of plasmids coincided with clonal expansion. Conclusions Our results highlight the recent concurrent expansion and geographical dissemination of CA MRSA clones across hospitals. These findings also underscore the interplay between clonal spread and horizontal gene transfer in shaping the resistance landscape of MRSA.

The authors have declared no competing interest.

This work was funded by KAUST faculty baseline fund (BAS/1/1108-01-01), KAUST baseline (BAS/1/1020-01-01)and KAUST FCC/1/5932-01-03 funds.

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This study received ethical approval from the Institutional Review Board (IRB) of King Abdullah University for Science and Technology (approval number 23IBEC027) and IRB of Saudi Ministry of Health (approval number: 23-23 M).

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Genomic data collected in this study were deposited in the European Nucleotide Archive (ENA) under the study accession number PRJEB71150. The assemblies were uploaded to the NCBI GenBank database under the accession number PRJNA1050907. Detailed metadata associated with the genomes are available in Supplemental Table S1. All the intermediate files and codes are provided in the GitHub directory for the project: www.github.com/gzhoubioinf/MOH_MRSA.