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生物膜群落，可以窝藏引起龋齿的生物体。变形链球菌群以变形链球菌和链球菌为代表。sobrinis是龋齿的主要病原体。龋齿是由变异链球菌的流行率增加引起的，变异链球菌将蔗糖代谢为乳酸，并产生酸性局部环境，使牙釉质脱矿并导致蛀牙。目前用于去除牙菌斑的方法影响病原体和微生物，并且可以改变口腔的生态平衡。尽管预防措施得到了广泛使用，但美国公众每年因蛀牙而花费的治疗费用超过580亿美元。显然，需要预防龋齿的新策略。一种防治龋齿的新策略包括防止变形链球菌定植在牙齿上并形成导致蛀牙的生物膜群落。我们已经确定并表征了一系列芳基绕丹宁，它们是革兰氏阳性菌（包括变形链球菌）中生物膜形成的有效抑制剂。重要的是，芳基绕丹宁不显示抗菌活性，并且对人上皮细胞没有细胞毒性。该提案的总体目标是鉴定特异性抑制S生物膜形成的芳基绕丹宁。这些化合物的可能应用将是口腔护理产品（例如牙膏或漱口水）的配制，其中芳基-绕丹宁将防止牙齿的酸化和随后由S.变形菌，但不是微生物。S.突变体特异性抗生物膜剂是一种预防龋齿的创新方法，并将对预防牙科的实践产生重大影响。在第一阶段，我们将筛选额外的芳基绕丹宁，特别是抑制生物膜形成的S。变种人，但 而非浮游生物，如S. gordonii和S.吸血鬼将基于抗生物膜效力和针对沙门氏菌的特异性对来自该筛选的确认命中进行优先级排序。变形菌、抗菌活性和细胞毒性。将在模拟口腔的条件下评价目标化合物的抗生物膜活性。并对芳基绕丹宁类化合物对S.变种人将被验证。本提案的具体目的如下：目的1，筛选现有的芳基绕丹宁（约1300种化合物）文库，以寻找抑制变形链球菌生物膜形成但不抑制变形链球菌生长的化合物;目的2，基于体外效力、对变形链球菌的特异性、对变形链球菌的特异性和对变形链球菌的特异性，优先选择抗生物膜化合物。目的3，确认芳基绕丹宁类化合物对S.变异人 公共卫生相关性：龋齿，俗称蛀牙，是人类最常见的传染病。牙菌斑是生长在牙齿表面的多物种生物膜群落，含有可导致蛀牙的生物体。龋齿是由变异链球菌的增加流行引起的，以变异链球菌和链球菌为代表。sobrinis，它将蔗糖代谢为乳酸，并创造一个酸性的局部环境，使牙釉质脱矿，导致蛀牙。尽管预防措施得到了广泛使用，但美国公众每年因蛀牙而花费的治疗费用超过580亿美元。显然，需要预防龋齿的新策略。该提案的总体目标是鉴定芳基绕丹宁，其特异性地抑制变形链球菌在牙齿上的定植，但不影响口腔的整体生态平衡。这些化合物的可能应用将是在制剂中， 口腔护理产品（例如牙膏或漱口水），其中芳基绕丹宁将防止牙齿的酸化和随后的S.变形菌，但不是微生物

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