Diversity supplement for R01DE029479-01A1 to support Dr. Jeremy Elias

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， 在调节pH值和防止酸引起的牙齿损伤方面至关重要。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/加重引起龋齿的酸产生。我们提出了四 具体目标是开发、识别和评估有效的t-TAB候选人。在具体目标1中，我们将合成 并表征了六种新的pH敏感性季铵盐（pH-QPSs）。我们希望能找出 或在含水混合物中提供t-TAB的化合物的组合。我们将加强对 化学结构/AM功效关系，并优化pH-QPS的AM功效和溶解度， 获得安全有效的t-TAB治疗。在具体目标2中，我们将授权一个经过临床测试的AM代理， 洗必泰（CHX），具有pH敏感的AM功效（pH-AM-E），并将其转化为t-TAB试剂。我们将 通过将CHX包封在QPS官能化的介孔二氧化硅中实现酸增强的CHX释放 纳米粒子我们还将鉴定由CHX和pH-QPS的相互作用诱导的协同pH-AM-E。在 具体目标3，我们将通过以下方式评估和比较目标1和目标2的主要候选药物的t-TAB疗效： 采用模拟人类口腔微生物群落的多物种生物膜模型（命名为O-mix）。那个 TAB疗效将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。 战略将需要评估生物量，分析微生物概况和确定环境pH值。最后， 成功抑制产龋菌生长的最有效的t-TAB候选物 同时使海藻类保持在工作条件下，例如，保持pH值高于5.5，将进一步 在特定目标4中使用体外微生物龋齿模型对人牙釉质进行体外评估， 采用成熟的小鼠龋齿模型。成功完成拟议目标将提供新的 用于牙科诊所的口腔冲洗材料，以预防/治疗龋齿。从这项研究中获得的知识也将 推进材料开发，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 facilitate a healthy microbial community that are vital in 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/aggravated caries-causing acid production in comparison to commensal species. We propose four specific aims to develop, identify and assess the 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 treatment. In Specific Aim 2, we will empower a clinically tested AM agent, chlorhexidine (CHX), with pH-sensitive AM efficacy (pH-AM-E) and transform it into a t-TAB agent. 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 while keeping the commensal species in working conditions, e.g., maintaining pH above 5.5, will be further assessed in Specific Aim 4 in vitro using an in vitro 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.