Preventing dental caries through targeted treatment of acid-producing bacteria

摘要：在当今的微生物时代，众所周知，龋病是最普遍和最昂贵的疾病之一 世界范围内的慢性传染病，由口腔微生物区系和口腔环境的失调引起 导致牙齿损伤的变化。具体地说，经常摄入可发酵的碳水化合物会促进 微生物组成逐渐向产酸和耐酸物种转移。连续不断的酸- 诱导脱矿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以下方式预防龋齿 产酸菌的靶向治疗(t-TAB)。T-TAB将促进健康的微生物群落， 对调节酸碱度和防止酸引起的牙齿损伤至关重要。T-TAB将通过选择性地实现 通过增强抗菌剂(AM)的效力来抑制致龋菌的生长 与共生物种相比，这些细菌的产酸速度更快。我们提出了四个具体的 旨在开发、确定和评估有效的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敏感的季铵盐(pH-QPS)。我们希望能鉴定出化合物或 在水混合物中提供t-TAB的化合物的组合。我们会加强对 化学结构/AM药效关系及优化AM药效和溶解度的pH-QPS(S)获得 安全有效的t-TAB治疗。在具体目标2中，我们将改造一种经过临床测试的AM制剂， 将洗必泰(CHX)转化为t-TAB试剂，可提供pH响应型AM药效。我们将实现酸化 通过包裹在QPS功能化介孔二氧化硅纳米颗粒中的CHX促进CHX的释放。我们 还将确定CHX和pH-QPS相互作用引起的pH-AM-E协同作用。在具体目标3中，我们 将使用多物种来评估和比较来自目标1和目标2的候选铅的t-TAB效率 模拟人类口腔微生物群落的生物膜模型(命名为O-Mix)。T-TAB的功效将是 在有无蔗糖的情况下进行评估，蔗糖是一种致龋性饮食碳水化合物。战略将需要 评估生物量，分析微生物谱，并确定环境pH。最后，最有效的 T-TAB候选化合物，成功抑制产龋酸细菌的生长，而不影响 共生物种的功能将在体外利用微生物-龋齿模型在特定目标4中进一步评估。 在人牙釉质和体内使用了一个成熟的小鼠龋齿模型。圆满完成 拟议的AIMS将为牙科诊所预防/治疗龋齿的口腔漱口提供新的材料。知识 这项研究还将促进材料的开发，以防止感染和侵蚀。

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.