Streptococcus mutans promotes a tooth-damaging dysbiosis in the oral microbiota because it can form biofilms and survive acid stress better than most of its ecological competitors, which are typically health associated. Many of these commensals produce hydrogen peroxide; therefore, S. mutans must manage both oxidative stress and acid stress with coordinated and complex physiological responses. In this study, the proteome of S. mutans was examined during regulated growth in acid and oxidative stresses as well as in deletion mutants with impaired oxidative stress phenotypes, Δnox and ΔtreR. A total of 607 proteins exhibited significantly different abundances across the conditions tested, and correlation network analysis identified modules of coexpressed proteins that were responsive to the deletion of nox and/or treR as well as acid and oxidative stress. The data explained the reactive oxygen species (ROS)-sensitive and mutacin-deficient phenotypes exhibited by the ΔtreR strain. SMU.1069-1070, a poorly understood LytTR system, had an elevated abundance in the ΔtreR strain. S. mutans LytTR systems regulate mutacin production and competence, which may explain how TreR affects mutacin production. Furthermore, the protein cluster that produces mutanobactin, a lipopeptide important in ROS tolerance, displayed a reduced abundance in the ΔtreR strain. The role of Nox as a keystone in the oxidative stress response was also emphasized. Crucially, this data set provides oral health researchers with a proteome atlas that will enable a more complete understanding of the S. mutans stress responses that are required for pathogenesis, and will facilitate the development of new and improved therapeutic approaches for dental caries. IMPORTANCE Dental caries is the most common chronic infectious disease worldwide and disproportionately affects marginalized socioeconomic groups. Streptococcus mutans is considered a primary etiological agent of caries, with its pathogenicity being dependent on coordinated physiological stress responses that mitigate the damage caused by the oxidative and acid stress common within dental plaque. In this study, the proteome of S. mutans was examined during growth in acidic and oxidative stresses as well in nox and treR deletion mutants. A total of 607 proteins were differentially expressed across the strains/growth conditions, and modules of coexpressed proteins were identified, which enabled mapping the acid and oxidative stress responses across S. mutans metabolism. The presence of TreR was linked to mutacin production via LytTR system signaling and to oxidative stress via mutanobactin production. The data provided by this study will guide future research elucidating S. mutans pathogenesis and developing improved preventative and treatment modalities for dental caries.

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