A new perspective on the antimicrobial mechanism of linezolid against Staphylococcus aureus revealed by proteomics and metabolomics analysis

Understanding bacterial responses to antimicrobials is crucial for identifying tolerance mechanisms and for developing new therapies. Using mass spectrometry–based metabolomics and proteomics, this study examines the response of Staphylococcus aureus to linezolid (LZD) treatment. Under LZD stress, significant fluctuations were observed in key metabolic pathways such as amino acid biosynthesis and the TCA cycle, alongside a general increase in ribosomal protein complexes. Additionally, LZD disrupted nucleotide metabolism, particularly affecting pyrimidine pathways. Combining LZD with the pyrimidine synthesis inhibitor leflunomide enhanced bactericidal effects both in vitro and in vivo, highlighting the importance of targeting pyrimidine biosynthesis to amplify the antimicrobial efficacy of protein inhibitors. These results underscore downstream metabolic processes as viable targets for synergistic drug combinations, suggesting a strategy to potentially improve the clinical effectiveness of LZD.