SloR-SRE binding to the S. mutans mntH promoter is cooperative.

Abstract

Streptococcus mutans is a commensal member of the plaque microbiome. It is especially prevalent when dietary sugars are available for S. mutans fermentation, generating acid byproducts that lower plaque pH and foster tooth decay. S. mutans can survive in the transient conditions of the mouth, in part because it can regulate the uptake of manganese and iron during periods of feast when metal ions are available, and famine when they are limited. S. mutans depends on a 25kDa metalloregulatory protein, called SloR, to modulate the uptake of these cations across the bacterial cell surface. When bound to manganese, SloR binds to palindromic recognition elements in the promoter of the sloABC genes that encode the major manganese transporter in S. mutans. Reports in the literature describe MntH, an ancillary manganese transporter in S. mutans, that is also subject to SloR control. In the present study, we performed expression profiling experiments that reveal coordinate regulation of the sloABC and mntH genes at the level of transcription. In addition, we describe a role for the mntH gene product that is redundant with that of the sloABC-encoded metal ion uptake machinery. The results of DNA-binding studies support direct SloR binding to the mntH promoter region which, like that at the sloABC promoter, harbors three palindromic recognition elements to which SloR binds cooperatively to repress downstream transcription. These findings expand our understanding of the SloR metalloregulome and elucidate SloR-DNA binding that is essential for S. mutans metal ion homeostasis and fitness in the oral cavity.

Importance: Dental caries disproportionately impacts low-income socioeconomic groups in the United States and abroad. Research that is focused on S. mutans, the primary causative agent of dental caries in humans, is significant to mitigation efforts aimed at alleviating or preventing dental caries. The SloR protein is a major regulator of the S. mutans metal ion uptake machinery encoded by the sloABC- and mntH genes. This SloR-mediated gene control is essential for maintaining intracellular metal ion homeostasis, and hence S. mutans fitness in the plaque microbiome. An improved understanding of the sloABC and mntH metal ion transporters and their regulation by SloR can guide rational drug design that, by targeting the SloR-DNA-binding interface, can alleviate or prevent S. mutans-induced disease.