Novel aryl-rhodanine inhibitors of Streptococcus mutans biofilms

描述（申请人提供）：龋齿，俗称蛀牙，是世界范围内严重的健康问题，是人类最常见的传染病之一。牙菌斑是生长在牙齿表面的一种生物膜群落，它可以容纳导致蛀牙的微生物。以变形链球菌和sobrinis为代表的变形链球菌群是引起龋齿的主要病原体。龋齿是由变形链球菌的增加引起的，它将蔗糖代谢成乳酸，并在局部形成酸性环境，使牙釉质脱矿，导致蛀牙。目前清除牙菌斑的方法对病原菌和共生菌都有影响，并且会改变口腔的生态平衡。尽管预防措施广泛使用，但美国公众每年用于治疗蛀牙的费用超过580亿美元。显然，我们需要新的策略来预防龋齿。一种对抗龋齿的新策略包括防止变形链球菌在牙齿上定植并形成导致蛀牙的生物膜群落。我们已经鉴定并鉴定了一系列芳基罗丹宁，它们是革兰氏阳性细菌（包括变形链球菌）生物膜形成的有效抑制剂。重要的是，芳基罗丹宁不表现出抗菌活性，对人上皮细胞没有细胞毒性。本提案的总体目标是确定特异性抑制变形链球菌生物膜形成的芳基罗丹宁，但不影响口腔生态平衡，这些化合物可能应用于口腔护理产品的配方（例如牙膏或漱口水），芳基罗丹宁将阻止变形链球菌在牙齿上的再定植和随后的生物膜形成，而不是共生生物。突变链球菌特异性抗生物膜剂的开发是预防龋齿的一种创新方法，将对预防性牙科的实践产生重大影响。在I期，我们将筛选其他特异性抑制变形链球菌生物膜形成的芳基罗丹宁，但是

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 would have 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 organisms that 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 that demineralizes 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 dental caries. 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