The genesis of dental caries is a process involving bacterial adhesion to pellicle, accumulation of bacteria, glucans and salivary proteins to form plaque, and finally the production of organic acids by the bacteria. The localized production of acid may result in the localized demineralization of the tooth. Interference in bacterial adhesion, accumulation, or acid production may prevent caries formation. The mutans streptococci are the primary causative agents of dental caries. The mutans streptococci utilize sucrose as a source of fermentable carbohydrate and as the substrate for D-glucan synthesis. The D-glucans are involved in the sucrose-dependent accumulation of streptococci on pellicle, and are considered to be virulence factors in caries formation. Inhibition of glucan formation should retard bacterial accumulation and aid the prevention of dental caries. Our past work has yielded sucrose derivatives which inhibit glucan synthesis by streptococcal glucosyltransferase (GTF) enzymes. Certain of these derivatives also inhibited bacterial adhesion and acid production. It is Planned to synthesize aldo and keto sucrose derivatives, tailored to be accommodated by the GTF active site, and to react irreversibly with nucleophilic groups on the enzymes. Also, new sucrose analogues designed to bind tightly and reversibly to GTF by mimicking reactive states along the GTF-sucrose reaction coordinate will be prepared. Further, enzyme-activated inhibitors for irreversible binding to the GTF active site will be prepared. Finally, oligosaccharide glucan mimics will be synthesized. Glucans are known to be bound by GTF with resultant alteration of enzyme activity. The results should further refine understanding of the structure and mode of action of GTF, permitting yet more effective inhibitors of glucan synthesis. Such inhibitors could ultimately be useful prophylactic aids in caries prevention, and two inhibitors have been selected for initial animal caries studies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE005102-11A2
Application #
3219243
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1978-04-01
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Medicine
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Cox, S D; Lassiter, M O; Taylor, K G et al. (1994) Fluoride inhibits the glucan-binding lectin of Streptococcus sobrinus. FEMS Microbiol Lett 123:331-4
McAlister, D; Doyle, R J; Taylor, K G (1989) Inhibition by maltose, isomaltose, and nigerose of the synthesis of high-molecular-weight D-glucans by the D-glucosyltransferases of Streptococcus sobrinus. Carbohydr Res 187:131-8
Oakley, J D; Taylor, K G; Doyle, R J (1985) Trypsin-susceptible cell surface characteristics of Streptococcus sanguis. Can J Microbiol 31:1103-7