Potentiation of fluoride toxicity in oral pathogens

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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.