Natural products in caries research: current (limited) knowledge, challenges and future perspective

Abstract

Dental caries is the most prevalent and costly oral infectious disease worldwide. Virulent biofilms firmly attached to tooth surfaces are prime biological factors associated with this disease. The formation of an exopolysaccharide-rich biofilm matrix, acidification of the milieu and persistent low pH at the tooth-biofilm interface are major controlling virulence factors that modulate dental caries pathogenesis. Each one offers a selective therapeutic target for prevention. Although fluoride, delivered in various modalities, remains the mainstay for the prevention of caries, additional approaches are required to enhance its effectiveness. Available antiplaque approaches are based on the use of broad-spectrum microbicidal agents, e.g. chlorhexidine. Natural products offer a rich source of structurally diverse substances with a wide range of biological activities, which could be useful for the development of alternative or adjunctive anticaries therapies. However, it is a challenging approach owing to complex chemistry and isolation procedures to derive active compounds from natural products. Furthermore, most of the studies have been focused on the general inhibitory effects on glucan synthesis as well as on bacterial metabolism and growth, often employing methods that do not address the pathophysiological aspects of the disease (e.g. bacteria in biofilms) and the length of exposure/retention in the mouth. Thus, the true value of natural products in caries prevention and/or their exact mechanisms of action remain largely unknown. Nevertheless, natural substances potentially active against virulent properties of cariogenic organisms have been identified. This review focuses on gaps in the current knowledge and presents a model for investigating the use of natural products in anticaries chemotherapy.

Fig. 1

Cariogenic biofilm formation (a–d) and potential targets (e) for disruption by natural products. a The Gtfs secreted by S. mutans are incorporated into pellicle (particularly GtfC) and adsorb on bacterial surfaces (mainly GtfB), including microorganisms that do not produce Gtfs (e.g. Actinomyces spp.). b Surface-adsorbed GtfB and GtfC rapidly utilize dietary sucrose (and starch hydrolysates) to synthesize insoluble and soluble glucans in situ; the soluble glucans formed by GtfD could serve as primers for GtfB enhancing overall synthesis of EPS. The Gtfs adsorbed onto enamel and microbial surfaces provide in situ an insoluble matrix for dental plaque-biofilm. Concomitantly, dietary carbohydrates (CHO) are metabolized into acids by acidogenic/aciduric organisms (e.g. S. mutans). c The glucan molecules provide avid binding sites on surfaces for S. mutans and other microorganisms mediating tight bacterial clustering and adherence to the tooth enamel (through glucan-glucan and glucan-Gbp interactions). Furthermore, Gtf-adsorbed bacteria de facto become glucan producers binding to tooth and microbial surfaces by the same mechanisms. This model could explain the rapid formation and accumulation of highly cohesive-adherent plaque in the presence of sucrose (and possibly starch) even if the number of S. mutans is relatively low. After the establishment of a glucan-rich biofilm matrix, ecological pressure (e.g. pH) will determine which bacteria may survive and dominate within plaque under frequent sucrose (or other fermentable carbohydrate) exposure. d If biofilm remains on tooth surfaces with frequent consumption of high-carbohydrate diet (especially sucrose), the amount of EPS and extent of acidification of the matrix will be increased. Such conditions cause biochemical, ecological and structural changes favoring the survival and dominance of highly acid stress-tolerant organisms in cohesive and firmly attached biofilms. The low-pH environment at the tooth-biofilm interface results in enhanced demineralization of enamel.

Fig. 2

Overview of the Suggested Model for Discovery of Naturally Occurring Anti-Caries Candidates.