Potentiation of fluoride toxicity in oral pathogens

氟化物对口腔病原体的毒性增强

• 批准号: 10652689
• 负责人: Livia Maria Andalo-Tenuta
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652689
• 关键词: Adult; Affect; Age; Antimicrobial Effect; Bacteria; Biochemical; Biodiversity; Biological Assay; Biosensor; Candida albicans; Chemicals; Chemosensitization; Child; Chlorhexidine; Communities; Consumption; Crude Extracts; Culture Media; Cytoplasm; Data; Dental caries; Development; Diet; Dietary Sugars; Disease; Ecology; Elderly; Electrophysiology (science); Exposure to; Family; Fluoride Ion; Fluorides; Gene Cluster; Genetic; Goals; Growth; Health; Hypersensitivity; Impairment; Individual; Informatics; Knock-out; Knowledge; Lesion; Libraries; Membrane Proteins; Metabolic; Metabolism; Microbe; Microbial Biofilms; Minerals; Modernization; Monitor; Morbidity - disease rate; Natural Products; Oral; Oral cavity; Oral health; Output; Pain; Pathogenicity; Patients; Periodicals; Persons; Physiological; Process; Productivity; Protein Export Pathway; Proteins; Quality of life; RNA; Risk; Role; Schools; Social Functioning; Sorting; Specificity; Streptococcus gordonii; Streptococcus mutans; Testing; Toothpaste; Toxic effect; Variant; Vulnerable Populations; Work; Yeasts; anticaries; antimicrobial; dental agent; dental biofilm; dysbiosis; economic impact; experimental study; fitness; fungus; genetic profiling; high throughput screening; improved; microbial; microbial composition; mortality; novel; novel therapeutics; nutrition; oral bacteria; oral biofilm; oral microbial community; oral pathogen; oral streptococci; physiologic model; polymicrobial biofilm; prevent; resistance mechanism; side effect; sugar

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.

项目总结/摘要 问题：龋齿是全球主要的健康状况，影响数十亿人， 疼痛、营养和社会功能受损、工作/学校生产力下降以及重大的经济损失 影响。对于最脆弱的群体，如儿童和老年人，以及患有高龋齿的个人 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 死亡是不可接受的。因为龋齿是由致龋菌代谢膳食糖引起的 生物膜，这是非常难以控制的;在现代饮食中广泛消费的可发酵糖有利于 致龋菌种如变形链球菌和牙齿中的机会性真菌白色念珠菌 生物膜，使龋齿过程永久化。氟化物是最有效的龋齿控制剂，但它具有非常 有限的抗菌作用，因为大多数微生物都有膜蛋白来排出氟化物， 在亚抑制水平的细胞内浓度。不同的口腔微生物物种具有不同类型的 氟输出菌; S. mutans和C.白色念珠菌分别采用CLCF和FEX蛋白，而有益的是， 口腔链球菌使用Fluc蛋白。这创造了一个机会，专门针对致病性口腔微生物 改变暴露于糖的生物膜中与健康相关的共生群落的物种动态， 氟化假设：我们假设氟输出蛋白可以被靶向用于抗菌 因此，本发明提供了一种有效的抗龋口腔细菌和真菌的药物组合物，同时保持有益的口腔微生物群完整。这 将在以下具体目标中检验假设：S.A.# 1：评价氟的竞争适合度 S. mutans和C.混合种属生物膜中的白色念珠菌 氟化物和pH值; S.A.# 2：确定天然产品，加强氟毒性致病口腔 微生物群意义：这些研究成果将为小说的发展奠定基础 龋齿治疗，加强氟离子的抗菌作用，以及提供新的基础， 了解氟的作用和微生物耐氟机制在社区动态中的作用 口腔微生物群