Small molecule inhibitors of cariogenic biofilms

致龋生物膜小分子抑制剂

• 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
• 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

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（蛀牙）是困扰美国公众的最普遍的传染病。生物膜 形成对于致龋细菌诱导的龋齿的发展至关重要。变形链球菌 是一种适应生物膜生活方式的致龋模型细菌。生物膜内的细菌极其 对传统抗生素和宿主防御具有抗药性；因此开发新型抗生物膜试剂 干扰致龋菌生物膜的形成和发育对于 龋齿的治疗和预防。最有效、最通用的抗生物膜分子 这些特性源自 Melander 小组发现的 2-氨基咪唑 (2-AI) 支架 天然海产品。 2-AI衍生物能够抑制和分散由以下物质形成的多种生物膜： 革兰氏阴性和革兰氏阳性细菌。在上一个融资周期中，我们取得了很大的进展，并且 鉴定并表征了两种不同的 2-AI 衍生物，它们可以抑制或分散变异链球菌致龋性 特别是生物膜。先导化合物不影响共生口腔链球菌的生物膜形成。我们的 研究表明，一种 2-AI 衍生物选择性地靶向调节变形链球菌的反应调节剂 生物膜、适应性和毒力。该化合物可抑制体外生物膜形成和体内细菌毒力 复杂的微生物群落，表明它具有巨大的治疗潜力。我们发现的另一种衍生物 在体外选择性地分散预先形成的变形链球菌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，这表明了一种新的潜在机制 机制。我们当前提案的目标是进一步探索这两类新的小分子， 定义它们的作用模式并开发更有效的、选择性的化学探针来剖析小分子 - 定向基因调控和信号传导是生物膜形成的关键。提出了两个具体目标： 具体目标1：探索选择性靶向致龋反应调节因子的分子机制 通过 2-AI 衍生物对细菌进行研究，并使用结构-活性关系研究和基于结构的药物 发现计划启发更有效和选择性化学探针的设计和开发 以增强抗龋活性。具体目标 2：确定有效小分子的分子靶标 分散致龋性变形链球菌生物膜并确定生物膜分散的潜在机制。一个 由微生物学家、药物化学家、结构生物学家、动物模型专家组成的跨学科团队， 和牙医科学家将继续富有成效的合作，这应该会解开分子机制 铅化合物如何选择性抑制和分散致龋生物膜并促进新材料的开发 防龋策略。该应用将直接影响广大民众的口腔健康 先导化合物在预防或治疗龋齿方面具有巨大的治疗潜力。