IMPORTANCE Polymicrobial diseases are the result of interactions among the residential microbes, which can lead to a dysbiotic community. Streptococcus sanguinis and Streptococcus gordonii are considered commensal species that are present in the healthy dental biofilm. Both species are able to produce significant amounts of H2O2 via the enzymatic action of the pyruvate oxidase SpxB. H2O2 is able to inhibit species associated with oral diseases. SpxB and its gene-regulatory elements present in both species are highly conserved. Nonetheless, a differential response to the presence of glucose was observed. Here, we investigate the mechanisms that lead to this differential response. Detailed knowledge of the regulatory mechanisms will aid in a better understanding of oral disease development and how to prevent dysbiosis.