A Small Molecule to Smile About: Identifying SloR-Binding Molecules as Potential Therapeutics for Dental Caries

Microbial dysbiosis in the oral cavity results in one of the most common infectious diseases in humans—dental caries. Despite current approaches to the prevention of caries, there is still an estimated $442 billion spent annually on costs associated with dental caries, indicating an unmet need for improved therapeutics. Streptococcus mutans is the primary causative agent of dental caries owing in large part to its extensive virulence arsenal that enables the gram-positive bacterium to adhere to the dentition, form thick biofilms, and to rapidly metabolize dietary carbohydrates into acid. S. mutans harbors a 25 kDa DNA-binding protein known as SloR that maintains homeostatic intracellular metal ion concentrations, allowing S. mutans to withstand the dynamic conditions of the oral cavity. SloR is a transcriptional repressor of many virulence genes, including the sloABC genes that encodes the metal ion uptake machinery of the bacterium. During mealtimes when manganese is readily available, SloR-Mn2+ complexes bind to so-called SloR recognition elements on the DNA to coordinate repression of the sloABC cassette. When manganese is limited (such as between mealtimes), SloR disengages from the DNA, thereby derepressing gene expression. In this study, we sought to use the principles of rational drug discovery to identify small molecules that encourage the SloR-DNA interaction, thereby reducing virulence gene expression and cariogenesis. We established an experimental pipeline that used virtual ligand screenings, cheminformatics, biolayer interferometry, growth curves, and the chloramphenicol acetyltransferase assay in order to discover a dental caries therapeutic. With this pipeline, we were able to identify and confirm a novel small molecule interactor of SloR, Domatinostat. The in silico portion of this study yielded a hit list of 10 promising small molecule candidates and delineated a common chemical scaffold as well as common R-groups that were predicted to bind SloR. The identification of a lead hit, the illumination of a SloR-binding pharmacophore, and the formulation of an effective experimental suite all represent a significant first step in the development of a dental caries therapeutic.