Dental caries is a costly disease characterized by the demineralization of the enamel, otherwise known as tooth decay. Despite advances in science, dental caries is the most common infectious disease worldwide and is increasing in incidence among young children. The etiologic causative agent of dental caries is Streptococcus mutans. Not only can S. mutans form biofilms readily on the tooth surface, but this bacterium rapidly produces lactic acid from dietary sugars. Dental caries cannot be easily treated with conventional antibiotics as cariogenic bacteria form tenacious biofilms, which are resistant to antibiotics. Current marketed therapies lack sensitivity;they are not species-specific and kill pathogenic species as well as commensal species, which are protective against the formation of pathogenic biofilms. In order to develop a therapeutic agent that is species specific for S. mutans, we constructed a diverse library of small molecules based on the structural motifs of bromoageliferin, a marine sponge product with antibiofilm and antibacterial properties. In a previous study, we utilized the library in a biofilm formation inhibition assay to identify potent small molecules that inhibit S. mutans biofilm formation specifically. Currently, we are redirecting our approach to focus on dispersing established S. mutans biofilms. By screening our library of small molecules with a biofilm dispersion assay, we identified 3F1 as a novel small molecule that selectively disperses S. mutans biofilms. While 3F1 dispersed approximately 50% of S. mutans biofilm, it did not disperse biofilms formed by commensal species Streptococcus sanguinis or Streptococcus gordonii. Confocal laser scanning microscopy images revealed that 3F1 altered the architecture of the biofilm by affecting the exopolymeric matrix, made evident through the reduced amount of exopolysaccharides. Glucosyltransferases (Gtfs) secreted by S. mutans are largely responsible for forming the exopolysaccharides which make up a large proportion of the exopolymeric matrix. The activity of 3F1 was not negated by the absence of the primary Gtf, GtfB, leading us to hypothesize that our small molecule induces the dispersal of S. mutans biofilms by interacting with a potentially unique and unknown mechanism related to the development and production of the exopolymeric matrix, which is necessary for biofilm maturation, structure, or maintenance. The identification of a novel target implicated in biofilm formation in S. mutans could potentially become a therapeutic target for the prevention or treatment of dental caries, while maintaining the commensal populations.
Dental caries, commonly known as tooth decay, is caused by the pathogenic bacterium, Streptococcus mutans. S. mutans can metabolize sucrose into insoluble- and soluble-glucans for use in the formation of the exopolymeric matrix of a biofilm- which provides resistance to common antibiotic therapy. As a by-product of sucrose metabolism, S. mutans secretes lactic acid, which leads to the demineralization of the enamel. These two points demonstrate the need to find a method of dispersing S. mutans biofilms.
|Garcia, S S; Blackledge, M S; Michalek, S et al. (2017) Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome. J Dent Res 96:807-814|
|Garcia, S S; Du, Q; Wu, H (2016) Streptococcus mutans copper chaperone, CopZ, is critical for biofilm formation and competitiveness. Mol Oral Microbiol 31:515-525|