Potentiation of fluoride toxicity in oral pathogens

项目摘要/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，以及显著的经济损失 影响。适用于最脆弱的群体，如儿童和老年人，以及高龋齿个人 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。因为龋齿是由一种致龋性食物糖类的新陈代谢引起的 生物膜，它很难控制；可发酵糖在现代饮食中的广泛消费有利于 牙齿中的致龋菌，如变形链球菌和机会真菌白色念珠菌 生物膜，使龋齿过程永久化。氟化物是最有效的防龋剂，但它有非常重要的作用。 抗菌作用有限，因为大多数微生物都有膜蛋白来排氟和保持 处于亚抑制水平的细胞内浓度。不同的口腔微生物种类具有不同类型的 氟化物输出子；变形链球菌和白色念珠菌分别使用CLCF和FEX蛋白，虽然有益 口腔链球菌使用Fluc蛋白。这创造了一个专门针对致病口腔微生物的机会 改变生物膜中与健康相关的共生群落的物种动力学，使其暴露于糖和 氟化物。假设：我们假设氟化物输出蛋白可以作为抗菌药物的靶点 抗龋齿口腔细菌和真菌的发展，同时保持有益的口腔微生物区系完整。这 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合性 变化条件下混合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：鉴定对致病口腔有增强氟化物毒性的天然产品 微生物区系。意义：这些研究的结果将为小说的发展奠定基础 增强氟离子抗菌作用的龋病治疗，以及提供新的基础 对氟化物的作用和微生物抗氟性机制在群落动态中的认识 口腔微生物区系。

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.