Abstract Staphylococcus aureus ST239 has been one of the most successful epidemic MRSA strains, and one of the leading causes of healthcare-associated MRSA infections. Here we investigate the evolution of ST239 using a combination of computational and experimental approaches. ST239 is thought to have emerged by a large scale chromosomal replacement event in which an ST8 clone acquired approximately 600 kb of DNA from an ST30 clone. Analysis of large-scale genomic data sets allowed us to confirm and refine the model of the origin of ST239. Importantly, we found that ST239 originated between the 1920s and 1945, implying that this MRSA lineage evolved at least 14 years before the clinical introduction of methicillin. Molecular evolution within ST239 has been dominated by purifying selection, although we found some evidence that the acquired region of the genome has evolved rapidly as a result of relaxed selective constraints. Crucially, we found that ST239 isolates have low competitive ability relative to both ST30 and ST8, demonstrating that this hybrid lineage is characterized by low fitness. We also found evidence of positive selection in a small number of genes involved in antibiotic resistance and virulence, suggesting that ST239 has evolved towards an increasingly pathogenic lifestyle. Collectively, these results support the view that low fitness has driven the recent decline of ST239, and highlight the challenge of using evolutionary approaches to understand the dynamics of pathogenic bacteria.

Evolutionary processes driving the rise and fall of Staphylococcus aureus ST239, a dominant hybrid pathogen