Tibetan Medicine Liuwei Dingxiang Pills Decoction Inhibits Pseudomonas aeruginosa via Fatty Acid Metabolic Reprogramming and Lipid Peroxidation Revealed by Untargeted Metabolomics

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Background: Pseudomonas aeruginosa is a major opportunistic pathogen and poses threat to public health. Traditional medicines are a valuable source of novel antibacterial agents. Liuwei Dingxiang Pills, a classical Tibetan formulation, have demonstrated clinical efficacy, but the antibacterial mechanisms remain unclear. This study evaluated the antibacterial effect and mechanism against P. aeruginosa via untargeted metabolomics. Methods: Minimum inhibitory concentration (MIC) were determined using agar diffusion and broth microdilution methods. Bacterial growth curves were plotted for different concentrations. Chemical constituents of the decoction and the bacterial metabolic profiles during the logarithmic phase were analyzed using high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Differential metabolites were annotated and assessed through KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Results: The decoction contained multiple bioactive compounds including gallic acid, homoorientin, corilagine, isovitexin, swertiamarin, isoalantolactone, coumarin, etc. It significantly inhibited all nine tested P. aeruginosa strains, with inhibition zones positively correlated with drug concentration. The MIC was 50 mg/mL. Untargeted metabolomics after sub-MIC treatment identified 346 differential metabolites ( p < 0.05), 281 were upregulated and 65 were downregulated. Notably, the oxidation products of linoleic acid (8-HPODE, 9/13-HODE, 9/13-OxoODE) and other derivatives 9,10-DHOME, 12,13-DHOME and γ-linolenic acid were significantly increased. Additionally, alpha-linolenic acid and traumatin in the α-linolenic acid pathway were also elevated. KEGG analysis indicated the activation of linolenic acid and α-linolenic acid metabolic pathways, suggesting that unsaturated fatty acid metabolism is the primary target of antibacterial action. Conclusion: Metabolomics analysis indicated that Liuwei Dingxiang Pills exert antibacterial effects through a mechanism involving multiple components and targets, synergistically inducing membrane disruption and endogenous oxidative stress, thereby triggering extensive linoleic acid-centered lipid peroxidation and metabolic reprogramming in P. aeruginosa . This novel mechanism provides theoretical basis for development of new antibacterial strategies targeting bacterial lipid metabolism. Keywords: Liuwei Dingxiang pills, Pseudomonas aeruginosa , antibacterial mechanism, metabolomics, lipid peroxidation

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