q orA shapes organ-specific adaptation of ST59-MRSA via balancing immune evasion and metabolic trade-off.

Sequence type 59 (ST59) is a predominant methicillin-resistant Staphylococcus aureus (MRSA) clone that causes invasive infections in Chinese hospitals. We performed weighted correlation network analysis on clinical MRSA and identified qorA as an ST59-specific redox regulator that sustains intracellular homeostasis by promoting NAD+-to-NADH conversion. Deletion of qorA impaired oxidative stress resistance; reduced the production of SodA, SodM, and staphyloxanthin; triggered metabolic reprogramming; and increased susceptibility to complement C3b deposition and neutrophil-mediated killing; these defects were partially rescued by the antioxidant N-acetylcysteine (NAC). Competitive murine infections demonstrated distinct organ-specific fitness: ΔqorA was outcompeted by the wild type in the liver and spleen but exhibited a fitness advantage in the heart, lungs, and kidneys, with comparable bacterial burdens in subcutaneous abscesses. Our findings indicate that qorA mediates organ-specific adaptation of ST59-MRSA by balancing immune evasion and metabolic trade-offs, highlighting its potential as a therapeutic target against S. aureus.