Human readaptation outpaces loss of antibiotic resistance in livestock-associated MRSA

Mobile genetic elements (MGEs) are agents of horizontal gene transfer in bacteria, but can also be vertically inherited by daughter cells. Establishing the dynamics that led to contemporary patterns of MGEs in bacterial genomes is central to predicting the emergence and evolution of novel and resistant pathogens. Here we develop existing methods to fully characterise the evolutionary history of MGEs in methicillin-resistant Staphylococcus aureus (MRSA) clonal-complex (CC) 398. CC398 is the dominant MRSA in European livestock, and a growing cause of human infections. We reconstruct MGE dynamics using a collection of 1,180 CC398 genomes, sampled from livestock and humans, over 27 years. We find that the emergence of livestock-associated CC398 coincided with the acquisition of a Tn 916 transposon carrying a tetracycline resistance gene, which has been stably vertically inherited for 57 years. This was followed by the acquisition of a type V SCC mec that carries methicillin, tetracycline and heavy metal resistance genes, which has been maintained by vertical and horizontal transmission for 35 years, with occasional truncations and replacements with type IV SCC mec . In contrast, a class of prophages that carry a human immune evasion gene cluster, that are largely absent from livestock-associated CC398, have been repeatedly gained and lost in both human- and livestock-associated CC398. These contrasting dynamics mean that when livestock-associated MRSA infects humans, adaptation to the human host outpaces loss of antibiotic resistance. In addition, stable inheritance means that antibiotic resistance in livestock-associated MRSA may persist despite ongoing reductions in antibiotic and zinc oxide use in farming. ### Competing Interest Statement The authors have declared no competing interest.