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.

翻译后摘要：在今天的微生物组时代，这是公认的，龋齿，最普遍和昂贵的 慢性感染性疾病是由口腔微生物群和口腔环境的生态失调引起的 导致牙齿损伤的变化。具体来说，频繁摄入可发酵碳水化合物会促进 微生物组成逐渐向产酸和耐酸物种转变。不断的酸- 诱导的脱矿作用最终克服了唾液的缓冲能力和抗微生物特性， 导致不可逆的牙齿破坏。这项拟议研究的目标是通过以下方法预防龋齿： 产酸细菌的靶向治疗（t-TAB）。t-TAB将促进健康的微生物群落， 对调节pH值和防止酸引起的牙齿损伤至关重要。t-TAB将通过选择性地 通过增强的抗微生物（AM）功效来抑制致龋细菌的生长， 加速了这些细菌的产酸。我们提出四个具体的 旨在开发，识别和评估有效的t-TAB候选人。在具体目标1中，我们将综合和 表征了六种新的pH敏感性季铵吡啶盐（pH-QPSs）。我们希望能鉴定出化合物， 在水性混合物中提供t-TAB的化合物的组合。我们会加强对 化学结构/AM功效关系，并优化pH-QPS（s）的AM功效和溶解度，以获得 安全有效的t-TAB治疗。在《特定目标2》中，我们将改造一个经过临床测试的AM代理， 氯己定（CHX）转化为提供pH响应性AM功效的t-TAB试剂。我们将实现酸 通过将CHX包封在QPS官能化的介孔二氧化硅纳米颗粒中来增强CHX释放。我们 还将鉴定由CHX和pH-QPS的相互作用诱导的协同pH-AM-E。在具体目标3中，我们 将通过采用多物种评估和比较目标1和目标2的主要候选物的t-TAB功效， 模拟人类口腔微生物群落的生物膜模型（命名为O-mix）。t-TAB疗效将是 在存在和不存在蔗糖-致龋膳食碳水化合物的情况下进行评估。战略将包括 评估生物量，分析微生物概况和确定环境pH值。最后， 成功抑制产龋细菌生长而不影响细菌生长的t-TAB候选物， 在《特定目标4》中，将使用微生物-龋齿模型在体外进一步评估牙菌斑物种的功能 在人牙釉质和体内采用发育良好的小鼠龋齿模型。成功完成 拟议的目标是为牙科诊所提供新的口腔冲洗材料，以预防/治疗龋齿。知识 从这项研究中获得的信息也将促进材料的发展，以防止感染和侵蚀。