Novel aryl-rhodanine inhibitors of Streptococcus mutans biofilms

变形链球菌生物膜的新型芳基绕丹宁抑制剂

• 批准号: 8393306
• 负责人: TIMOTHY J OPPERMAN
• 金额: $ 16.82万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393306
• 关键词: Adhesions; Affect; American; Anti-Bacterial Agents; Bacteria; Binding; Biocide; Biological Assay; Cell Line; Communicable Diseases; Communities; Data; Dental Enamel; Dental Plaque; Dental caries; Dentistry; Development; Drug Design; Drug Formulations; Enterococcus; Environment; Epithelial Cells; Equilibrium; Excision; Exhibits; Genus staphylococcus; Goals; Gram-Positive Bacteria; Growth; Health; Human; In Vitro; Lactic acid; Lead; Libraries; Measures; Mechanics; Methods; Microbial Biofilms; Mouthwash; Oral; Oral cavity; Organism; Phase; Prevalence; Rhodanine; Saliva; Series; Specific qualifier value; Specificity; Streptococcus gordonii; Streptococcus mitis; Streptococcus mutans; Streptococcus oralis; Sucrose; Surface; Tooth structure; Toothpaste; analog; base; combat; cost; cytotoxic; cytotoxicity; design; in vivo; inhibitor/antagonist; innovation; interest; meetings; microbial; novel; novel strategies; oral biofilm; oral care; pathogen; prevent; tooth surface

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

描述(申请人提供)：龋齿，俗称龋齿，是全世界严重的健康问题，也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，可能含有导致龋齿的微生物。以变形链球菌和远缘链球菌为代表的变形链球菌群是引起龋病的主要致病菌。龋齿是由变形链球菌的流行引起的，变形链球菌将蔗糖代谢成乳酸，并创造出酸性的局部环境，使牙釉质脱矿，导致龋齿。目前去除牙菌斑的方法影响病原菌和共生菌，并可能改变口腔的生态平衡。尽管广泛使用预防措施，但美国公众每年花费超过580亿美元用于治疗龋齿。显然，需要新的策略来预防龋齿。一种新的防治龋齿的策略包括防止变形链球菌定植牙齿和形成导致龋齿的生物膜群落。我们已经鉴定并表征了一系列芳基罗丹宁，它们是包括变形链球菌在内的革兰氏阳性细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，并且对人类上皮细胞没有细胞毒性。这项建议的总体目标是确定芳基罗丹宁能够特异性地抑制变形链球菌的生物被膜形成，但不影响口腔的生态平衡。这些化合物可能应用于口腔护理产品(如牙膏或漱口水)的配方中，其中芳基罗丹宁将防止牙齿重新繁殖和随后由变形链球菌形成生物膜，但不能防止共生生物。针对变形链球菌的抗生物被膜剂的开发是预防龋齿的一种创新方法，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罗丹宁，这些芳基罗丹宁专门抑制变形链球菌的生物膜形成，但 而不是戈登氏链球菌和血链球菌等共生生物。从这个屏幕上确认的点击将根据抗生物膜的效力和对变形链球菌的特异性、抗菌活性和细胞毒性来排序。在模拟口腔的条件下，将评估感兴趣的化合物的抗生物被膜活性。芳基罗丹宁对变形链球菌的作用机制将得到验证。这项建议的具体目的如下：目标1，筛选现有的芳基罗丹宁文库(~1300种化合物)，以寻找抑制变形链球菌生物被膜形成但不抑制浮游生长的化合物；目标2，基于体外效力、对变形链球菌的特异性和细胞毒性，优先选择抗生物被膜化合物；以及目标3，确认芳基罗丹宁与变形链球菌的抗生物膜活性的作用机制。 与公共卫生相关：龋齿，俗称龋齿，是人类最常见的传染病。牙菌斑是生长在牙齿表面的一种多物种生物膜群落，含有可能导致龋齿的微生物。龋齿是由以变形链球菌和远缘链球菌为代表的变形链球菌的流行引起的，变形链球菌将蔗糖代谢成乳酸，并创造出酸性的局部环境，使牙釉质脱矿，导致龋齿。尽管广泛使用预防措施，但美国公众每年花费超过580亿美元用于治疗龋齿。显然，需要新的策略来预防龋齿。这项建议的总体目标是确定芳基罗丹宁，专门抑制变形链球菌对牙齿的定植，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配方中 口腔护理产品(如牙膏或漱口水)，其中芳基罗丹宁将防止牙齿重新繁殖和随后由变形链球菌形成生物膜，但不能防止共生生物