SMU_1361c regulates the oxidative stress response of Streptococcus mutans

Dental caries is the most common chronic infectious disease around the world and disproportionately affects the marginalized socioeconomic group. Streptococcus mutans, considered a primary etiological agent of caries, depends on the coordinated physiological response to tolerate the oxidative stress generated by commensal species within dental plaque, which is a critical aspect of its pathogenicity. Here, we identified and characterized a novel tetracycline repressor family regulator, SMU_1361c, which appears to be acquired by the bacteria via horizontal gene transfer. Surprisingly, smu_1361c functions as a negative transcriptional regulator to regulate gene expression outside its operon and is involved in the oxidative stress response of S. mutans. The smu_1361c overexpression strain UA159/pDL278-1361c was more susceptible to oxidative stress and less competitive against hydrogen peroxide generated by commensal species Streptococcus gordonii and Streptococcus sanguinis. Transcriptomics analysis revealed that smu_1361c overexpression resulted in the significant downregulation of 22 genes, mainly belonging to three gene clusters responsible for the oxidative stress response. The conversed DNA binding motif of SMU_1361c was determined by electrophoretic mobility shift and DNase I footprinting assay with purified SMU_1361c protein; therefore, smu_1361c is directly involved in gene transcription related to the oxidative stress response. Crucially, our finding provides a new understanding of how S. mutans deals with the oxidative stress that is required for pathogenesis and will facilitate the development of new and improved therapeutic approaches for dental caries. IMPORTANCE Streptococcus mutans is the major organism associated with the development of dental caries, which globally is the most common chronic disease. To persist and survive in biofilms, S. mutans must compete with commensal species that occupy the same ecological niche. Here, we uncover a novel molecular mechanism of how tetracycline repressor family regulator smu_1361c is involved in the oxidative stress response through transcriptomics analysis, electrophoretic mobility shift assay, and DNase I footprinting assay. Furthermore, we demonstrated that smu_1361c mediates S. mutans sensitivity to oxidative stress and competitiveness with commensal streptococci. Therefore, this study has revealed a previously unknown regulation between smu_1361c and genes outside its operon and demonstrated the importance of smu_1361c in the oxidative stress response and the fitness of S. mutans within the plaque biofilms, which can be exploited as a new therapy to modulate ecological homeostasis and prevent dental caries.