All ETDs from UAB

Advisory Committee Chair

Sadanandan E Velu

Advisory Committee Members

Subramaniam Ananthan

Eugenia Kharlampieva

Pengfei Wang

Hui Wu

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Streptococcus mutans is the primary cariogenic agent of dental caries. This bacterium has developed numerous mechanisms to attach to tooth surfaces and initi-ate the proliferation of biofilms. In addition, S. mutans contributes to the acidification of the oral cavity, as it produces lactic acid from dietary sugars, which ensues tooth decay. Currently marketed caries therapies do not selectively kill cariogenic species, instead they disrupt the whole natural oral flora in the oral cavity including the beneficial species. In order to develop a species specific therapeutic agent, we have targeted the S. mutans glucosyltransferases (Gtfs) for our structure-based drug design. These enzymes metabolize sucrose into water insoluble and soluble glucans, which play a role in mediat-ing irreversible attachment of S. mutans to the tooth surface and also provide an extracel-lular matrix, shielding the bacteria from the host immune response, and antimicrobial agents. In silico screening of commercially available compound databases against the crystal structure of the GtfC and the screening of natural products such as chalcones, stil-benes, aurones, and flavonols in S. mutans biofilm assays resulted in the identification of several lead compounds as potential Gtf inhibitors. In vitro assays showed that the com-pounds were capable of inhibiting glucan synthesis and biofilm formation in S. mutans by selectively inhibiting Gtfs instead of by killing the bacteria directly. The binding kinetics of these inhibitors was characterized using OctetRed for some of the lead compounds. iv Moreover, the synthetic leads significantly reduced the incidence and severity of smooth surface caries in vivo. Subsequently, we have synthesized libraries of compounds to con-duct structure activity relationship studies in an effort to optimize the activity of the lead scaffolds. Thus, this dissertation provides an overview of the identification and develop-ment of novel, selective, anti-biofilm therapeutics amenable for the treatment and preven-tion of dental caries.

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