Potentiation of fluoride toxicity in oral pathogens

项目概要/摘要 问题：龋齿是全球主要的健康问题，影响着数十亿人并导致 疼痛、营养和社会功能受损、工作/学校生产力下降以及显着的经济损失 影响。对于最脆弱的群体，例如儿童和老年人以及患有高龋齿的人 所有年龄段的风险、这种疾病的后果——包括生活质量下降、发病率甚至 死亡率——是不可接受的。因为龋齿是由于食物中的糖类被致龋物质代谢而引起的。 生物膜，很难控制；现代饮食中发酵糖的广泛消费有利于 致龋菌种，例如牙齿中的变形链球菌和机会性真菌白色念珠菌 生物膜，使龋齿过程永久化。氟化物是最有效的防龋剂，但它的作用非常有限。 抗菌效果有限，因为大多数微生物都有膜蛋白来排出氟化物并保持 细胞内浓度处于亚抑制水平。不同的口腔微生物物种具有不同类型的 氟化物出口国；变形链球菌和白色念珠菌分别使用 CLCF 和 FEX 蛋白，同时有益 口腔链球菌使用Fluc蛋白。这创造了专门针对口腔致病微生物的机会 改变暴露于糖和生物膜中与健康相关的共生群落的物种动态 氟化物。假设：我们假设氟化物输出蛋白可以作为抗菌的目标 针对致龋口腔细菌和真菌的开发，同时保持有益的口腔微生物群完整。这个 假设将在以下具体目标中进行检验：S.A.#1：评估氟化物的竞争适应性 变化条件下混合物种生物膜中变形链球菌和白色念珠菌的出口缺陷菌株 氟化物和 pH 值； S.A.#2：识别增强氟化物对口腔致病菌毒性的天然产物 microbiota.意义：这些研究结果将为新型药物的开发奠定基础 龋齿治疗可增强氟离子的抗菌作用，并提供新的基础 关于氟化物和微生物氟化物抗性机制在群落动态中的作用的知识 口腔微生物群。

PROJECT SUMMARY/ABSTRACT The problem: Dental caries is the leading health condition worldwide, affecting billions of people and causing pain, impaired nutrition and social functioning, reduction in work/school productivity, and significant economic impacts. For the most vulnerable groups, such as children and older adults, and individuals with high caries risk of all ages, the consequences of this disease – including a reduced quality of life, morbidity and even mortality – are unacceptable. Because caries is caused by the metabolism of dietary sugars by a cariogenic biofilm, it is very difficult to control; the widespread consumption of fermentable sugars in modern diets favors cariogenic species such as Streptococcus mutans and the opportunistic fungi Candida albicans in the dental biofilm, perpetuating the caries process. Fluoride is the most effective agent for caries control, but it has very limited antimicrobial effects because most microbes have membrane proteins to expel fluoride and keep intracellular concentrations at sub-inhibitory levels. Different oral microbial species possess different types of fluoride exporters; S. mutans and C. albicans employ CLCF and FEX proteins, respectively, while beneficial oral streptococci use Fluc proteins. This creates an opportunity to specifically target pathogenic oral microbes to modify species dynamics towards health-associated symbiotic communities in biofilms exposed to sugar and fluoride. Hypothesis: We hypothesize that fluoride export proteins can be targeted for antimicrobial development against cariogenic oral bacteria and fungi, while leaving beneficial oral microbiota intact. This hypothesis will be tested in the following specific aims: S.A.#1: To evaluate the competitive fitness of fluoride export-deficient strains of S. mutans and C. albicans in mixed-species biofilms under conditions of changing fluoride and pH; S.A.#2: To identify natural products that potentiate fluoride toxicity for pathogenic oral microbiota. Significance: The results of these studies will establish groundwork for the development of novel caries treatments that potentiate the antimicrobial effects of fluoride ion, as well as provide new basic knowledge about the role of fluoride and microbial fluoride resistance mechanisms in community dynamics of the oral microbiota.