A GC-MS-based untargeted metabolomics approach for comprehensive metabolic profiling of vancomycin-induced toxicity in mice

Background: Vancomycin is a glycopeptide antibiotic that is commonly used for severe drug-resistant infections treatment. Application of vancomycin frequently leads to severe ototoxicity, hepatotoxicity, and nephrotoxicity; however, the comprehensive metabolic analysis of vancomycin-induced toxicity is lacking.Purpose: This study attempted to investigate the metabolic changes after vancomycin administration in mice.Methods: Experimental mice (n = 9) received continuous intraperitoneal injection of vancomycin (400 mg/kg) every day for 7 days, and mice in control group (n = 9) were treated with the same amount of normal saline. Pathological changes of the kidney were examined using haematoxylin and eosin (HE) staining. A gas chromatography-mass spectrometry (GC-MS) approach was used to identify discriminant metabolites in serum and various organs including the heart, liver, kidney, spleen, cerebral cortex, hippocampus, inner ear, lung, and intestine. The potential metabolites were identified using orthogonal partial least squares discrimination analysis (OPLS-DA). Subsequently, the MetaboAnalyst 5.0 (http://www.metaboanalyst.ca) and Kyoto Encyclopedia of Genes and Genomes database (KEGG, http://www.kegg.jp) were employed to depict the metabolic pathways.Results: Compared with the control group, the vancomycin induced 13, 17, 27, 22, 16, 10, 17, 11, 10, and 7 differential metabolites in the serum, liver, kidney, heart, cerebral cortex, lung, spleen, intestine, hippocampus, and inner ear, respectively. Further pathway analyses identified that amino acids metabolism, fatty acids biosynthesis, energy metabolism, and lipid metabolism were disrupted after VCM exposure.Conclusion: Vancomycin affects the metabolism in various organs in mice, which provides new insights for identification of vancomycin-induced toxicity, and facilitate to better understanding of the metabolic patho-genesis of vancomycin.