ABSTRACT 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.
Shen et al. (2026) studied this question.