Master transcriptional regulator SaeS in <i>Staphylococcus aureus</i> contributes to staphyloxanthin biosynthesis to promote survival during invasive infection

<i>Staphylococcus aureus</i> is a major human opportunistic pathogen that causes significant morbidity and mortality, particularly in immunocompromised individuals. SaeRS is a two-component system in <i>S. aureus</i> that regulates signal transduction related to virulence, including hemolysis and coagulation. Metal ions are essential nutrients that support bacterial virulence and survival against host immune cells and are intricately interconnected with regulatory systems. The SaeRS system has long been studied for its function in bacterial virulence and invasive infections. However, its interactions with other regulators and metal ions remain unelucidated. Thus, this study evaluated the effects of the <i>S. aureus</i> SaeRS system on virulence, specifically its association with oxidative stress resistance and staphyloxanthin (STX) production. <i>saeS</i> deletion reduced STX production via the SigB-CrtOPQMN pathway, increasing vulnerability to oxidative stress and susceptibility to host immune cells. Supplementation with metal ions, specifically zinc, inhibited STX-associated gene expression, attenuating antioxidative activity <i>in vitro</i>. Experiments on mice with <i>S. aureus</i> bloodstream infection verified that SaeS was crucial for bacterial survival <i>in vivo</i>. Furthermore, zinc contributed to weakened bacterial virulence and altered host immune defense mechanisms. Collectively, our results established a novel mechanistic interconnection between SaeRS and STX biosynthesis and demonstrated that SaeRS inhibition combined with zinc supplementation promotes innate immune system-mediated killing of <i>S. aureus</i>.