Targeting of Staphyloxanthin and α‐Hemolysin by Natural Compound L‐Malic Acid Suppresses <i>Staphylococcus aureus</i> Virulence

The escalating prevalence of antibiotic resistance in Staphylococcus aureus has underscored the urgent necessity for groundbreaking anti-infective therapies that target novel pathways. Metabolic intermediates, such as those in the TCA cycle, have been known to be linked to bacterial virulence. L-Malic acid (L-MA), a natural TCA cycle intermediate, is known for its antimicrobial and antioxidant properties; however, its effect on the virulence of Staphylococcus aureus has yet to be explored. It was found that L-malic acid not only inhibited bacterial growth but also markedly reduced the production of crucial virulence factors, including staphyloxanthin and α-hemolysin. The suppression of pigment synthesis was primarily due to the competitive antagonism of CrtO, a key oxidoreductase responsible for carotenoid biosynthesis in Staphylococcus aureus, coupled with enhanced flux through the TCA cycle that redirected acetyl-CoA pools away from the mevalonate pathway. Moreover, hemolytic activity was decreased by lowering the expression of α-hemolysin. In vivo studies using mouse infection models further demonstrated that L-malic acid effectively mitigated the pathogenicity of Staphylococcus aureus, significantly reducing the formation of skin and liver abscesses. These findings position L-malic acid as a promising agent targeting Staphylococcus aureus infections, highlighting the need for further research into its therapeutic potential.