Preventing dental caries through targeted treatment of acid-producing bacteria

通过针对性治疗产酸菌预防龋齿

• 批准号: 10474963
• 负责人: Xuesong He
• 金额: $ 72.09万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10474963
• 关键词: Acids; Advanced Development; Affect; Animal Model; Antimicrobial Effect; Bacteria; Biomass; Buffers; Carbohydrates; Carbon; Caries prevention; Chemical Structure; Chemistry; Chlorhexidine; Chronic; Clinical; Collaborations; Communicable Diseases; Consequentialism; Dental Clinics; Dental Enamel; Dental caries; Development; Dietary Carbohydrates; Effectiveness; Encapsulated; Equilibrium; Feedback; Future; Goals; Growth; Human; In Vitro; Infection prevention; Intake; Kinetics; Knowledge; Length; Microbial Biofilms; Modeling; Monitor; Mus; Names; Oral; Particle Size; Physiological; Production; Property; Research; Saliva; Salts; Series; Silicon Dioxide; Sodium Chloride; Solubility; Stimulus; Streptococcus mutans; Sucrose; Surface; Tail; Testing; Tooth structure; Translating; Water; acronyms; analog; antimicrobial; antimicrobial drug; aqueous; bactericide; base; biomaterial compatibility; cariogenic bacteria; cost; demineralization; design; dysbiosis; effectiveness evaluation; environmental change; improved; in vivo; innovation; lead candidate; microbial; microbial community; microbial composition; microbiome; multidisciplinary; nanoparticle; novel; oral microbial community; polymicrobial biofilm; polymicrobial disease; prevent; research clinical testing; response; targeted treatment; water solubility

Abstract: In today's microbiome era, it is well-recognized that dental caries, one of the most prevalent and costly chronic infectious diseases world-wide, results from dysbiosis of the oral microbiota and the oral environmental changes that cause tooth damage. Specifically, frequent intake of fermentable carbohydrates promotes a progressive shift in microbial composition toward acidogenic and acid-tolerant species. The continual acid- induced demineralization eventually overcomes the buffering capacity and anti-microbial properties of saliva, leading to irreversible tooth destruction. The goal of this proposed research is to prevent dental caries through targeted treatment of acid-producing bacteria (t-TAB). t-TAB will promote a healthy microbial community that is vital for modulating pH and preventing acid-induced teeth damage. The t-TAB will be achieved by selectively inhibiting the growth of cariogenic bacteria through enhanced antimicrobial (AM) efficacy in response to the accelerated acid production by these bacteria in comparison to commensal species. We propose four specific aims to develop, identify and assess effective t-TAB candidates. In Specific Aim 1, we will synthesize and characterize six new pH-sensitive quaternary pyridinium salts (pH-QPSs). We expect to identify compounds or combinations of compounds that provide t-TAB in aqueous mixtures. We will enhance our understanding of the chemical structure/AM efficacy relationship and optimize the AM efficacy and solubility of pH-QPS(s) to obtain safe and effective t-TAB treatments. In Specific Aim 2, we will transform a clinically tested AM agent, chlorhexidine (CHX), into a t-TAB agent which provides pH-responsive AM efficacy. We will achieve acid enhanced CHX release through encapsulated CHX in QPS-functionalized mesoporous silica nanoparticles. We will also identify the synergistic pH-AM-E induced by interactions of CHX and pH-QPSs. In Specific Aim 3, we will assess and compare the t-TAB efficacy of lead candidates from Aim 1 and Aim 2 by employing a multispecies biofilm model that simulates human oral microbial community (named O-mix). The t-TAB efficacy will be assessed in the presence and absence of sucrose—the cariogenic dietary carbohydrate. Strategy will entail evaluating biomass, analyzing microbial profiles and determining environmental pH. Finally, the most effective t-TAB candidates that successfully inhibit the growth of cariogenic acid-producing bacteria without affecting the functions of commensal species will be further assessed in Specific Aim 4 in vitro using a microbial-caries model on human enamel and in vivo employing a well-developed mouse caries model. Successful completion of the proposed aims will provide new materials for oral rinse in dental clinics to prevent/treat dental caries. Knowledge gained from this study will also advance material development to prevent infection and erosion.

摘要：在当今的微生物组时代，人们认识到龋齿是最普遍，最昂贵的牙齿之一 全世界的慢性传染病，口腔菌群的营养不良和口腔环境引起的 改变牙齿损坏的变化。具体而言，经常摄入可发酵的碳水化合物会促进 微生物组成向酸性和耐酸物种进行了逐步转移。连续酸 - 诱导的脱矿化最终克服了唾液的缓冲能力和抗微生物特性， 导致不可逆转的牙齿破坏。这项拟议研究的目的是防止龋齿通过 靶向产生酸性细菌（T-TAB）的靶向治疗。 T-TAB将促进一个健康的微生物社区 对于调节pH值和防止酸引起的牙齿损伤至关重要。 t-tab将通过选择性实现 通过增强的抗菌（AM）效率来抑制致肉源性细菌的生长 与共生物种相比，这些细菌加速酸的产生。我们提出了四个特定的 旨在开发，识别和评估有效的T-TAB候选者。在特定目标1中，我们将合成并 表征了六个新的pH敏感的四肾盐（pH-QPSS）。我们希望识别化合物或 在水性混合物中提供T-tab的化合物组合。我们将增强我们对 化学结构/AM效率关系，并优化pH-QP的AM效率和溶解度以获得 安全有效的T-TAB治疗。在特定的目标2中，我们将改变经过临床测试的AM代理， 氯己定（CHX）成T-tab剂，可提供pH响应式AM效率。我们将达到酸 通过在QPS功能化介孔二氧化硅纳米颗粒中封装的CHX增强了CHX的释放。我们 还将确定由CHX和pH-QPS相互作用引起的协同pH-AM-E。在特定的目标3中，我们 将评估和比较AIM 1的铅候选者的t-tab效率，并通过使用多种产品来进行AIM 2 模拟人类口腔微生物群落的生物膜模型（命名为O-Mix）。 T-tab效率将是 在存在和不存在蔗糖的情况下进行评估（碳饮食中的碳饮食）。策略将需要 评估生物量，分析微生物谱并确定环境pH值。最后，最有效 t-tab候选者成功抑制了产生酸性细菌的生长而不会影响 使用微生物 - 卡里斯模型，将在特定目标4中进一步评估共生物种的功能 在人体搪瓷和体内采用了良好的小鼠携带模型。成功完成 拟议的目标将为牙科诊所提供口腔冲洗的新材料，以预防/治疗龋齿。知识 从这项研究中获得的还将推进材料的发展，以防止感染和侵蚀。