Advisory Committee Chair
Sadanandan E Velu
Advisory Committee Members
Champion Deivanayagam
Eugenia Kharlampieva
Jessica Scofield
Gayan Wijeratne
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Dental caries, a highly prevalent disease, is characterized by the erosion of the tooth surface. This disease is caused by the oral bacteria living in complex communities called biofilms. Streptococcus mutans, among the various pathogenic bacterial species inhabiting the oral cavity, is considered to be the major etiological agent for dental caries. This bacterium forms robust biofilms capable of producing significant amounts of acid, leading to the demineralization of hydroxyapatite in the tooth enamel and subsequent erosion over time. Biofilm penetration into the dentin and pulp causes severe pain, while the entry of the bacteria into the bloodstream can result in severe complications, including sepsis and potential fatality. iv S. mutans adhere to the tooth surface and attach to other bacteria in the oral cavity using sucrose-dependent and sucrose-independent adhesion mechanisms. In the sucroseindependent mechanism, the bacteria utilize surface proteins such as antigen I/II, to recognize and bind to salivary agglutinin (SAG) proteins present in the salivary pellicle of the tooth surface. In the sucrose-dependent mechanism, S. mutans employs a set of surfacesecreted proteins called glucosyltransferases (Gtfs). These enzymes catalyze the synthesis of glucose oligomers called glucans, which have the ability to bind to the bacterial cell surface through another set of surface proteins known as glucan binding proteins (GBP). Glucans also contribute to the formation of an exopolysaccharide matrix, providing architectural support to the biofilms and acting as a nutrient reservoir for the bacteria within the biofilm. This enables the bacteria to form three-dimensional, robust, and tenacious biofilms. Consequently, Gtfs are considered as targets for the therapeutic development against dental caries. Saliva employs buffering mechanisms to maintain a healthy physiological pH of 7.0 - 7.5 and prevent dental erosion, but this system fails when acidogenic bacteria such as S. mutans produce excessive amounts of acid. Under cariogenic conditions, the lactic acid produced by pathogenic bacteria shifts the balance of oral pH to lower than 5.5 causing the demineralization of tooth. The work described in this Ph. D. thesis focuses on the design and development of selective inhibitors of S. mutans biofilm formation while preserving the planktonic growth of oral commensal bacterial flora. Optimized lead biofilm inhibitors with in vitro and in vivo anticariogenic activity were identified through structure-based drug design and lead optimization studies. The optimized lead compound HA5 was then encapsulated into pHresponsive hydrogel to generate hydrogel-encapsulated biofilm inhibitor (HEBI) for the v pH-responsive drug delivery. The in vitro and in vivo evaluation of anticariogenic activity of HEBI is also presented. Overall, the data presented in this thesis suggests that the biofilm-specific therapy using S. mutans biofilm inhibitors or HEBI reported here is a viable approach for prevention and treatment of dental caries while preserving the oral microbiome.
Recommended Citation
Ahirwar, Parmanand, "Streptococcus Mutans Biofilm Inhibiting Small Molecules with Anticariogenic Activity" (2023). All ETDs from UAB. 453.
https://digitalcommons.library.uab.edu/etd-collection/453
