Evolutionary route of resistant genes in Staphylococcus aureus

Multi-drug resistant S. aureus is a leading concern worldwide. Coagulase-Negative Staphylococci (CoNS) are claimed to be the reservoir and source of important resistant elements in S. aureus . However, the origin and evolutionary route of resistant genes in S. aureus are still remaining unknown. Here, we performed a detailed phylogenomic analysis of 152 completely sequenced S. aureus strains in comparison with 7,529 non- S. aureus reference bacterial genomes. Our results reveal s that S. aureus has a large open pan-genome where 97 (55%) of its known resistant related genes belonging to its accessory genome. Among these genes, 47 (27%) were located within the Staphylococcal Cassette Chromosome (SCCmec), a transposable element responsible for resistance against major classes of antibiotics including beta-lactams, macrolides and aminoglycosides. However, the physically linked mec-box genes ( MecA-MecR-MecI) that are responsible for the maintenance of SCCmec elements is not unique to S. aureus , instead it is widely distributed within Staphylococcaceae family. The phyletic patterns of SCCmec encoded resistant genes in Staphylococcus species are significantly different from that of its core genes indicating frequent exchange of these genes between Staphylococcus species. Our in-depth analysis of SCCmec resistant gene phylogenies reveals that genes such as blaZ , ble, kmA and tetK that are responsible for beta-lactam, bleomycin, kanamycin and tetracycline resistance in S. aureus were laterally transferred from non- Staphylococcus sources. In addition, at least 11 non-SCCmec encoded resistant genes in S. aureus , mostly present in plasmid are laterally acquired from distantly related species. Our study evidently shows that gene transfers played a crucial role in shaping the evolution of antibiotic resistance in S. aureus .