Expression patterns of core metabolic genes and elevated intracellular ROS confer drug tolerance in <i>Staphylococcus aureus</i>

<i>S. aureus</i> poses a major public health threat due to its remarkable ability to develop antibiotic tolerance, often leading to treatment failure and resistance emergence. This study provides critical insights into the underlying metabolic mechanisms. Proteomic analysis revealed that different genetic mutations in tolerant isolates converged on similar gene expression changes, which directly impacted the tolerance phenotype. Notably, the tolerant strains exhibited elevated intracellular reactive oxygen species (ROS) levels, and ROS scavenger treatment increased their antibiotic susceptibility. These findings demonstrate that shifts in core metabolic gene expression are pivotal for <i>S. aureus</i> to withstand antibiotic stress, with ROS metabolism regulation being a central component of the broader metabolic adaptations conferring drug tolerance. Understanding these metabolic underpinnings is crucial for developing more effective treatments against persistent, tolerant <i>S. aureus</i> infections. The identified metabolic targets and ROS-modulating approaches offer promising strategies to combat escalating antibiotic resistance.