Metabolomics Analysis Provides Insights into the Antibacterial Activity of Curcumin-Based Photodynamic Treatment Against Staphylococcus aureus

<i>Staphylococcus aureus</i> is a major foodborne pathogen that poses persistent challenges to food safety. Antimicrobial photodynamic treatment (PDT) has emerged as a promising non-thermal antimicrobial strategy capable of effectively inactivating <i>S. aureus</i>, though accumulating evidence suggests that the bacteria may initiate adaptive responses to the PDT or even develop tolerance. However, the metabolic mechanisms underlying bacterial responses to PDT exposure, particularly under sub-lethal conditions, remain poorly understood. Thus, in the current study, untargeted metabolomics based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS) were employed to characterize intracellular metabolic alterations in <i>S. aureus</i> following curcumin-mediated PDT (40 µM curcumin, 425 nm blue light at intensity of 0.198 J cm^-2). The obtained results revealed a clear separation between the control and PDT-treated groups, indicating sub-lethal PDT induced pronounced metabolic perturbations while preserving partial cellular viability. A total of 97 significantly differential metabolites were identified, encompassing a range of key metabolites associated with amino acid biosynthesis, lipid metabolism, and nucleotide metabolism, indicating the PDT-induced metabolic alterations in pathways could be associated with stress adaptation, membrane integrity, and energy metabolism. Collectively, these findings demonstrate that PDT, even at sub-lethal doses, induces extensive metabolic dysregulation in <i>S. aureus</i>, which potentially represent critical bactericidal vulnerability points target by PDT, yet may paradoxically participate in adaptive metabolic responses that support bacterial survival under PDT exposure. Further investigations are therefore warranted to elucidate the relationships among PDT-induced metabolic perturbations, bacterial inactivation, and long-term phenotypic adaptation. Overall, this work may provide mechanistic insight into PDT-induced antimicrobial action and support further optimization of PDT as an effective non-thermal intervention for food safety and preservation.