Bacterial metabolic remodeling by convergent evolution unlocks nutrient availability after a host switch

New pathogens typically arise from host jump events between species. Staphylococcus aureus is a multihost pathogen responsible for a global burden of human disease and a leading cause of intramammary infection in dairy cattle. Here, we demonstrate that following historical human-to-bovine host switch events, S. aureus has undergone adaptive metabolic remodeling in response to distinct nutrient availability in the dairy niche. In particular, we found that bovine S. aureus has evolved the capacity for protease-mediated degradation of casein, a protein abundant in bovine milk, to access nutrients for proliferation. This phenotype has evolved convergently in different S. aureus lineages via mutations in distinct gene loci driving overexpression of the protease aureolysin. Together, we have dissected a key host-adaptive trait, which facilitates the enzymatic release of nutrients from a substrate specific to the new host milieu. These findings highlight the remarkable evolutionary plasticity of a major bacterial pathogen underpinning its multihost species tropism.