Small molecule inhibitors of cariogenic biofilms

致龋生物膜小分子抑制剂

基本信息

批准号：
10226712
负责人：
Christian Corey Melander
金额：
$ 49.83万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226712
关键词：
Acids Age American Animal Model Antibiotics Bacteria Biochemical Biochemical Pathway Biology Caries prevention Chemicals Clinical Research Clinical Trials Collaborations Communicable Diseases Communities Complex Consumption Dental Enamel Dental Models Dental caries Dentists Development Diet Dietary Factors Etiology Evaluation Family Funding Future Gene Expression Regulation General Population Genetic Goals Gram-Negative Bacteria Gram-Positive Bacteria Host Defense Human In Vitro Lactic acid Lead Lesion Life Style Manuscripts Microbial Biofilms Microbial Genetics Modeling Molecular Molecular Target Odontogenesis Oral health Pathway interactions Positioning Attribute Prevention strategy Property Proteins Publishing Rattus Reagent Resistance Scheme Scientist Signal Transduction Streptococcus mutans Structural Biologist Structure Structure-Activity Relationship Sucrose Systems Biology Therapeutic Tooth Demineralization Vaccines Virulence analog anticaries bacterial fitness base cariogenic bacteria clinical translation combat conventional therapy cost dental biofilm design drug discovery dysbiosis early childhood effective therapy experience fitness human disease improved in silico in vivo interdisciplinary approach marine natural product microbial community novel oral bacteria oral commensal oral microbial community oral streptococci physical insult pre-clinical prevent response scaffold small molecule small molecule inhibitor tooth surface transcription factor treatment strategy

项目摘要

Abstract Dental caries (tooth decay) is the most prevalent infectious disease afflicting American Public. Biofilm formation is crucial for the development of dental caries induced by cariogenic bacteria. Streptococcus mutans is a model cariogenic bacterium that has adapted to the biofilm lifestyle. Bacteria within a biofilm are extremely resistant to traditional antibiotics and host defense; therefore development of new classes of anti-biofilm reagents that interfere with the biofilm formation and development by cariogenic bacteria is necessary and critical for the treatment and prevention of dental caries. The most potent and versatile class of molecules with anti-biofilm properties are those derived from the 2-aminoimidazole (2-AI) scaffold discovered by the Melander group from natural marine products. The 2-AI derivative is capable of inhibiting and dispersing diverse biofilms formed by Gram-negative and Gram-positive bacteria. In the last funding cycle, we have made great progress, and identified and characterized two distinct 2-AI derivatives that either inhibit or disperse S. mutans cariogenic biofilms specifically. The lead compounds do not affect biofilm formation by commensal oral streptococci. Our studies have shown that one 2-AI derivative selectively targets a response regulator that modulates S. mutans biofilm, fitness and virulence. The compound inhibits biofilm formation in vitro and bacterial virulence in vivo in the complex microbial community, indicating it has great therapeutic potential. Another derivative we identified selectively disperses preformed S. mutans biofilms in vitro and inhibits bacterial colonization and virulence in vivo. The dispersion activity is not mediated by any known biofilm pathway, suggesting a novel underlying mechanism. The goal of our current proposal is to further explore these two new classes of small molecules, define their modes of action and develop more potent, selective chemical probes to dissect small molecules- directed gene regulation and signaling that are key to biofilm development. Two specific aims are proposed: Specific Aim 1: Explore molecular mechanisms of selective targeting of the response regulator of cariogenic bacteria by the 2-AI derivative and use both structure-activity relationship studies, and structure-based drug discovery schemes to enlighten the design and the development of more potent and selective chemical probes to enhance anti-cariogenic activity. Specific Aim 2: Identify molecular targets of the potent small molecule that disperses cariogenic S. mutans biofilms and determine the underlying mechanism of the biofilm dispersion. An interdisciplinary team among microbiologists, medicinal chemists, structural biologists, animal model experts, and dentist scientists will continue their productive collaborations, which should unravel molecular mechanisms how lead compounds selectively inhibit and disperse cariogenic biofilms and facilitate the development of new anti-caries strategies. The application will have a direct impact on the oral health of the general public since the lead compounds have great therapeutic potentials in preventing or treating dental caries.

抽象的龋齿（牙齿衰减）是困扰着美国公众的最普遍的传染病。生物膜形成对于致癌细菌诱导的龋齿的发展至关重要。链球菌突变是一种适合生物膜生活方式的型号的致蛋白细菌。生物膜内的细菌极为对传统抗生素和宿主防御的抵抗力；因此开发了新的抗生物胶片试剂这种干扰性菌细菌的生物膜形成和发育是必要的，对于治疗和预防龋齿。具有抗生物膜的最有效和多功能的分子类属性是源自梅兰德集团发现的2-氨基咪唑（2-ai）脚手架的属性天然海洋产品。 2-AI衍生物能够抑制和分散由多种生物膜形成的生物膜革兰氏阴性和革兰氏阳性细菌。在最后一个资金周期中，我们取得了巨大进步，并且鉴定并表征了两个不同的2-AI衍生物，这些衍生物抑制或分散链球菌的杂种性葡萄糖性衍生物特定生物膜。铅化合物不会影响共生口服链球菌的生物膜形成。我们的研究表明，一个2-AA衍生物有选择地靶向调节链球菌的响应调节剂生物膜，健身和毒力。该化合物在体外抑制了体外的生物膜形成和细菌毒力复杂的微生物社区，表明它具有巨大的治疗潜力。我们确定的另一个导数选择性地分散了体外繁殖链球菌的生物膜，并抑制细菌定植和毒力体内。分散活性不是由任何已知的生物膜途径介导的，这表明了一个新颖的基础机制。我们当前建议的目的是进一步探索这两个新类的小分子，即定义其作用方式，并产生更有效的选择性化学探针，以剖析小分子 - 定向基因调控和信号传导是生物膜发育的关键。提出了两个具体目标：特定目的1：探索致癌响应调节剂的选择性靶向的分子机制通过2-AI衍生物细菌，并使用结构活性关系研究和基于结构的药物启发更有效和选择性化学探针的设计和开发的发现方案增强抗钙化活性。特定目标2：确定有效的小分子的分子靶标的分散致癌链球菌生物膜并确定生物膜分散剂的潜在机制。一个微生物学家，药物学家，结构生物学家，动物模型专家，跨学科团队，牙医科学家将继续其生产性合作，这应揭示分子机制铅化合物如何有选择地抑制和分散致癌生物膜并促进新的发展反卡里人策略。该申请将对公众的口腔健康产生直接影响，因为铅化合物在预防或治疗龋齿方面具有巨大的治疗潜力。