Disruption of ytrE attenuates methicillin-resistant Staphylococcus aureus virulence and compromises membrane integrity and oxidative stress resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of invasive infections, yet the genetic basis of its stress adaptation remains partially understood. This study investigates the role of the conserved membrane-associated gene ytrE in MRSA USA300 pathogenesis. While disruption of ytrE did not affect in vitro growth or biofilm formation, the ΔytrE mutant exhibited significant attenuation in a murine systemic infection model, characterized by increased host survival and reduced bacterial burdens in major organs. Phenotypic analyses revealed that loss of ytrE leads to compromised membrane integrity, impaired surface-associated motility, and heightened sensitivity to oxidative stress (H2O2). Furthermore, the mutant showed reduced levels of cell-associated phenol-soluble modulins (PSMs), which may contribute to the impaired colony spreading phenotype. Genetic complementation restored the major altered phenotypes observed in the ΔytrE mutant. These findings suggest that ytrE contributes to MRSA pathogenic fitness by supporting envelope homeostasis and resistance to oxidative stress. Non-essential factors involved in membrane stability may represent potential targets for future anti-virulence studies.