The USA300 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) lineage causes the majority of skin and soft tissue infections (SSTIs) and is highly associated with the carriage of the arginine catabolic mobile element (ACME). However, the contribution of ACME to USA300's success in SSTIs is not completely understood. We show that the constitutive ACME-encoded arginine-deiminase system (Arc) allows USA300 to thrive in acidic environments that mimic human skin. Consequently, the ACME-Arc system drives excessive production of host polyamines, compounds uniquely toxic to S. aureus. To mitigate this, ACME also encodes SpeG, a polyamine-resistance enzyme that is essential for combating excess host polyamines in a murine SSTI model. Inhibiting host polyamine production not only restored ΔspeG persistence within infected wounds but also severely altered the host healing process, implying that polyamines play an integral role in coordinating the wound-healing response. Together, these data underscore the functional modularity of ACME and its contribution to the success of USA300 CA-MRSA.
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