Novel aryl-rhodanine inhibitors of Streptococcus mutans biofilms

DESCRIPTION (provided by applicant): Dental caries, commonly known as tooth decay, is a serious health problem all over the world, and is one of the most common infectious diseases in humans. Dental plaque, a biofilm community growing on the tooth surface,can harbor organisms that cause dental caries. The mutans streptococcal group, represented by Streptococcus mutans and S. sobrinis, are the major causative agents of dental caries. Dental caries is initiated by increased prevalence of mutans streptococci,which metabolize sucrose to lactic acid and create an acidic local environment that demineralizes tooth enamel and causes tooth decay. Current methods for removal of dental plaque affect both pathogenic and commensal organisms and can alter ecological balance of the oral cavity. Despite the widespread use of preventative measures, tooth decay costs the American public more than 58 billion annually for treatment. Clearly, there is a need for novel strategies for preventing dental caries. A novel strategy for combating dental caries consists of preventing the mutans streptococci from colonizing teeth and forming the biofilm communities that cause tooth decay. We have identified and characterized a series of aryl-rhodanines that are potent inhibitors of biofilm formation in Gram-positive bacteria, including Streptococcus mutans. Importantly, the aryl-rhodanines do not exhibit antibacterial activity and are not cytotoxic against human epithelial cells. The overall goal of this proposal is to identify aryl-rhodanines that specificall inhibit biofilm formation of S. mutans, but do not affect the ecological balance of the oral cavity The likely application of these compounds will be in the formulation of oral care products (e.g. toothpaste or mouthwashes), where aryl-rhodanines will prevent recolonization of the teeth and subsequent biofilm formation by S. mutans, but not commensal organisms. The development of an S. mutans-specific anti-biofilm agent is an innovative approach to preventing dental caries, and wouldhave a significant impact on the practice of preventative dentistry. In Phase I, we will screen for additional aryl-rhodanines that specifically inhibit biofilm formation in S. mutans, but not the commensal organisms, such as S. gordonii and S. sanguinis.The confirmed hits from this screen will be prioritized based on anti-biofilm potency and specificity against S. mutans, antibacterial activity, and cytotoxicity. Compounds of interest will be evaluated for anti-biofilm activity under conditions that mimic the oral cavity. The mechanism of action of the aryl-rhodanines against S. mutans will be verified. The specific aims of this proposal are as follows: Aim 1, Screen an existing library of aryl rhodanines (~1300 compounds) for compounds that inhibit biofilm formation, but not planktonic growth, of Streptococcus mutans; Aim 2, Prioritize anti-biofilm compounds based on in vitro potency, specificity for S. mutans, and cytotoxicity; and Aim 3, Confirm the mechanism of action of the anti-biofilm activity of aryl rhodanines vs. S. mutans. PUBLIC HEALTH RELEVANCE: Dental caries, commonly known as tooth decay, the most common infectious diseases in humans. Dental plaque, a multispecies biofilm community growing on the surfaces of teeth, contains organismsthat can cause tooth decay. Dental caries is initiated by increased prevalence of bacteria known as mutans streptococci, typified by Streptococcus mutans and S. sobrinis, which metabolize sucrose to lactic acid and creates an acidic local environment thatdemineralizes tooth enamel and causes tooth decay. Despite the widespread use of preventative measures, tooth decay costs the American public more than 58 billion annually for treatment. Clearly, there is a need for novel strategies for preventing dentalcaries. The overall goal of this proposal is to identify aryl-rhodanines that specifically inhibit colonization of teeth by the mutans streptococci, but do not affect the overall ecological balance of the oral cavity. The likely application of these compounds will be in the formulation of oral care products (e.g. toothpaste or mouthwashes), where aryl-rhodanines will prevent recolonization of the teeth and subsequent biofilm formation by S. mutans, but not commensal organisms