Multi-omic analysis reveals lysine acylation and biofilm formation induced by central metabolites in...

Methicillin-resistant Staphylococcus aureus (MRSA) is a major multidrug-resistant pathogen responsible for severe infections, such as pneumonia and bloodstream infections. These infections are often associated with high mortality rates and pose a significant burden on public health. Studies have shown that biofilm formation is a key factor contributing to its enhanced drug resistance. Recent evidence also implicates core metabolites in biofilm regulation. However, their specific regulatory mechanisms remain unclear. In this study, we initially assessed how key metabolites from glycolysis and the tricarboxylic acid (TCA) cycle influenced MRSA physiology. Notably, glucose markedly enhanced bacterial proliferation and stimulated biofilm development. To further explore the molecular basis of glucose-induced changes in MRSA, we subsequently applied a multidimensional omics approach, including proteomics, acetylomics, succinylomics, and lactylomics. A total of 1666 proteins, 3761 lysine acetylated sites, 1809 succinylated sites, and 128 lactylated sites were identified by high-resolution mass spectrometry. Subsequent bioinformatic analysis revealed that these modifications were significantly enriched in ribosome-associated functions and metabolic pathways. To further explore their functional relevance, in vitro enzyme assays demonstrated that glucose-induced lysine succinylation modulates the activity of arsenate reductase. Building upon this, functional validation at both the bacterial and host cell levels confirmed the physiological significance of glucose-induced lysine acylation. In conclusion, these findings reveal that the core metabolite glucose promotes MRSA biofilm formation and induces extensive lysine acylation, which in turn regulates metabolic functions and virulence. Therefore, this study provides new insights into MRSA pathogenesis and suggests potential targets for anti-infective therapy.