Identification of a novel gene argJ involved in arginine biosynthesis critical for persister formation in Staphylococcus aureus

Staphylococcus aureus can cause both acute and recurrent persistent infections such as peritonitis, endocarditis, abscess, osteomyelitis, and chronic wound infections. An effective treatment to eradicate the persistent disease is still lacking as the mechanisms of S. aureus persistence are poorly understood. In this study, we performed a comprehensive and unbiased high-throughput mutant screen using S. aureus USA300 and identified argJ, encoding an acetyltransferase in the arginine biosynthesis pathway, whose mutation produced a significant defect in persister formation in multiple drugs and stresses. Genetic complementation and arginine supplementation restored persistence in the ArgJ mutant. Quantitative real-time PCR analysis showed that the arg genes were over-expressed under drug stressed conditions and in stationary phase cultures. In addition, the ArgJ mutant had attenuated virulence in both C. elegans and mouse models of infection. Our studies identify a novel mechanism of persistence mediated by arginine metabolism in S. aureus. These findings will not only provide new insights about the mechanisms of S. aureus persistence but also offer novel therapeutic targets that may help to develop more effective treatment of persistent S. aureus infections.