Preventing dental caries through targeted treatment of acid-producing bacteria

通过针对性治疗产酸菌预防龋齿

基本信息

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
项目类别：
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

项目摘要

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，众所周知，龋齿是最普遍和最昂贵的疾病之一。世界范围内的慢性传染病，是由口腔微生物群和口腔环境失调引起的具体来说，频繁摄入可发酵碳水化合物会导致牙齿损伤。微生物组成逐渐转向产酸和耐酸物种。诱导的脱矿质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标是通过预防龋齿。产酸细菌（t-TAB）的靶向治疗将促进健康的微生物群落。 t-TAB 对于调节 pH 值和酸引起的牙齿损伤至关重要。通过增强抗菌 (AM) 功效来抑制致龋菌的生长与共生菌相比，我们提出了四种特定的细菌产酸速度。旨在开发、识别和评估有效的 t-TAB 候选者。在具体目标 1 中，我们将综合和评估。我们希望鉴定出六种新的 pH 敏感季吡啶盐 (pH-QPS) 的特征。我们将加深对在水性混合物中提供 t-TAB 的化合物的组合的了解。化学结构/AM功效关系并优化pH-QPS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，我们将改造经过临床测试的 AM 制剂，将氯己定 (CHX) 转化为 t-TAB 剂，提供 pH 响应性 AM 功效。通过将 CHX 封装在 QPS 功能化介孔二氧化硅纳米粒子中，增强 CHX 释放。还将确定 CHX 和 pH-QPS 相互作用诱导的协同 pH-AM-E。在特定目标 3 中，我们。将通过采用多物种来评估和比较目标 1 和目标 2 中主要候选药物的 t-TAB 功效模拟人类口腔微生物群落的生物膜模型（称为 O-mix）的 t-TAB 功效将为。在存在和不存在蔗糖的情况下进行评估——致龋膳食碳水化合物策略将需要进行。最后，评估生物量、分析微生物特征并确定环境 pH 值。 t-TAB 候选物可成功抑制致龋酸产生细菌的生长，而不影响将在特定目标 4 中使用微生物龋齿模型在体外进一步评估共生物种的功能使用成熟的小鼠龋齿模型成功完成了对人类牙釉质和体内的研究。拟议的目标将为牙科诊所口腔冲洗提供新材料，以预防/治疗龋齿。这项研究的成果还将促进防止感染和侵蚀的材料开发。