The raw research data for manuscript titled "DSR2 Delactylates Pgk to Regulate Growth and Cariogenicity of S. mutans"

Lysine lactylation (Kla) is an emerging post-translational modification that links cellular metabolism with protein function. We previously demonstrated that lysine lactylation in the model cariogenic pathogen Streptococcus mutans serves as a critical regulatory mechanism governing biofilm formation and extracellular polysaccharide synthesis. However, the specific enzymatic machinery responsible for reversing this modification in S. mutans remains unknown. Here, we identify defense-associated sirtuin 2 (DSR2) as a multifunctional lysine deacylase with prominent delactylase activity. Using quantitative proteomics in Streptococcus mutans, we mapped 258 endogenous Kla sites across 134 proteins targeted by DSR2, revealing a global regulatory network centered on central carbon metabolism. Mechanistically, we demonstrate that DSR2-mediated delactylation of phosphoglycerate kinase (Pgk) at the conserved Lys208 residue significantly represses its catalytic activity, thereby serving as a metabolic rheostat to modulate glycolysis and bacterial proliferation. Leveraging this discovery, a small-molecule screen identified LY377604 as a potent inhibitor that targets the Pgk-K208 site, effectively suppressing S. mutans growth and alleviating dental caries in a rat model. Collectively, these findings identify DSR2-mediated delactylation of Pgk as a regulatory mechanism for S. mutans growth and cariogenicity and support the DSR2-Pgk axis as a potential anti-S. mutans target for further study.