AdhE Regulates the Adaptation Ability of Streptococcus mutans to Oxidative Stress and Heat Stress

ABSTRACT Understanding how S. mutans adapts to environmental stresses is key to deciphering its cariogenic virulence. Here, we report that alcohol‐acetaldehyde dehydrogenase (AdhE) modulates the stress adaptability in S. mutans by regulating a metabolic‐acetylation axis. We demonstrated that overexpression of adhE sensitizes S. mutans to H 2 O 2 and high temperature, impairing planktonic growth and biofilm integrity under oxidative and heat stress. Mechanistically, AdhE functions as a potential acetyl‐CoA (Ac‐CoA) synthase, with its overexpression elevating intracellular Ac‐CoA levels. Quantitative acetylomics revealed that elevated Ac‐CoA drives extensive protein acetylation, hyperacetylating 340 proteins. Protein interaction network analysis identified core antioxidant enzymes (Tpx, Dpr, TrxA/B, AhpC) and heat‐shock chaperones (DnaJ, GroEL, ClpE) as major targets, linking hyperacetylation to compromised stress defenses. Crucially, in a rat caries model, adhE overexpression attenuated the cariogenic virulence of S. mutans , reducing oral colonization and caries severity, an effect exacerbated by H 2 O 2 challenge. Collectively, these findings uncover AdhE as a metabolic regulator that bridges Ac‐CoA availability, global protein acetylation, and stress adaptation, offering new insights into posttranslational control of bacterial fitness and potential anti‑caries targets.