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The microbes that inhabit the human oral cavity are subjected to constant fluctuations in their environment. To overcome these challenges and gain a competitive advantage, oral streptococci employ numerous adaptive strategies, many of which appear to be intertwined with the development of genetic competence. Here, we demonstrate that the regulatory circuits that control development of competence in  Streptococcus mutans , a primary etiological agent of human dental caries, are integrated with key stress tolerance pathways by the molecular alarmone (p)ppGpp. We first observed that the growth of a strain that does not produce (p)ppGpp (Δ relAPQ , (p)ppGpp 0 ) is not sensitive to growth inhibition by  com X    i nducing  p eptide (XIP), unlike the wild-type strain UA159, even though XIP-dependent activation of the alternative sigma factor  comX  by the ComRS pathway is not impaired in the (p)ppGpp 0  strain. Overexpression of a (p)ppGpp synthase gene ( relP ) in the (p)ppGpp 0  mutant restored growth inhibition by XIP. We also demonstrate that exposure to micromolar concentrations of XIP elicited changes in (p)ppGpp accumulation in UA159. Loss of the RelA/SpoT homolog (RSH) enzyme, RelA, lead to higher basal levels of (p)ppGpp accumulation, but to decreased sensitivity to XIP and to decreases in  comR  promoter activity and ComX protein levels. By introducing single amino acid substitutions into the RelA enzyme, the hydrolase activity of the enzyme was shown to be crucial for full  com  gene induction and transformation by XIP. Finally, loss of  relA  resulted in phenotypic changes to Δ rcrR  mutants, highlighted by restoration of transformation and ComX protein production in the otherwise non-transformable Δ rcrR -NP mutant. Thus, RelA activity and its influence on (p)ppGpp pools appears to modulate competence signaling and development through RcrRPQ and the peptide effectors encoded within  rcrQ . Collectively, this study provides new insights into the molecular mechanisms that integrate intercellular communication with the physiological status of the cells and the regulation of key virulence-related phenotypes in  S. mutans .

An Essential Role for (p)ppGpp in the Integration of Stress Tolerance, Peptide Signaling, and Competence Development in Streptococcus mutans