Therapeutic Strategies Targeting Cariogenic Biofilm Microenvironment

Abstract

Cariogenic biofilms are highly structured microbial communities embedded in an extracellular matrix, a multifunctional scaffold that is essential for the existence of the biofilm lifestyle and full expression of virulence. The extracellular matrix provides the physical and biological properties that enhance biofilm adhesion and cohesion, as well as create a diffusion-modulating milieu, protecting the resident microbes and facilitating the formation of localized acidic pH niches. These biochemical properties pose significant challenges for the development of effective antibiofilm therapeutics to control dental caries. Conventional approaches focusing solely on antimicrobial activity or enhancing remineralization may not achieve maximal efficacy within the complex biofilm microenvironment. Recent approaches disrupting the biofilm microbial community and the microenvironment have emerged, including specific targeting of cariogenic pathogens, modulation of biofilm pH, and synergistic combination of bacterial killing and matrix degradation. Furthermore, new "smart" nanotechnologies that trigger drug release or activation in response to acidic pH are being developed that could enhance the efficacy of current and prospective chemical modalities. Therapeutic strategies that can locally disrupt the pathogenic niche by targeting the biofilm structure and its microenvironment to eliminate the embedded microorganism and facilitate the action of remineralizing agents may lead to enhanced and precise anticaries approaches.

Keywords: EPS; acidic pH; antibiofilm therapeutics; dental caries; matrix; nanotechnology.

Figure 1.

The matrix and targets of current and prospective antibiofilm approaches. The matrix is a “multifunctional scaffold” essential for biofilm lifestyle, which benefits its entire life cycle from initial microbial colonization and accumulation to biofilm maturation. Therapeutic strategies can be designed to (I) promote healthy oral communities on teeth by favoring the colonization and/or fitness of commensal organisms against cariogenic pathogens. If conditions are conducive to development of dental caries (e.g., sugar-rich diet), exopolysaccharides (EPS)–mediated bacterial adhesion-cohesion and further accumulation ensues, (II) promoting the initiation of cariogenic biofilms (III), which would require EPS-targeting strategies in addition to antimicrobials against increasing proportions of cariogenic pathogens. Once mature biofilm is established (IV), more aggressive measures, including physical disruption and EPS matrix degradation combined with antimicrobials, may be needed to enhance access and killing efficacy against the embedded bacteria.

Figure 2.

Structure and function of pH-activated nanocarrier for antibiofilm drug delivery. Scheme depicting (A) the self-assembly of diblock copolymers that results in cationic polymeric nanoparticle carrier (nanocarrier) of around 21 nm. The polymer conjugation and its subsequent physicochemical features results in a positively charged hydrophilic outer surface and hydrophobic core, in which hydrophobic antibacterial agent (e.g., farnesol) can be incorporated. The pH-responsive core expedites drug release at acidic pH. (B) The nanocarrier has high affinity to both the pellicle and exopolysaccharide matrix (multisite affinity). Microchemical environment changes toward an acidic pH trigger farnesol release and bacterial killing within biofilms. Adapted from Horev et al. (2015) with the permission of the American Chemical Society. The nanocarrier design and biofilm diagrams were designed by Michael Osadciw/University of Rochester. EPS, exopolysaccharides.

Figure 3.

Schematics of biofilm disruption under acidic condition by catalytic nanoparticle (CAT-NP) activation of hydrogen peroxide (H₂O₂). (1) CAT-NPs bind and retain within biofilm despite brief topical exposure, making them suitable for a topical treatment regimen typically used in oral care products; (2) the enzyme-like activity is pH responsive, rapidly catalyzing low concentrations of H₂O₂ at acidic pH to produce free radicals that simultaneously (3) degrade biofilm matrix and (4) kill embedded bacteria. Furthermore, (5) CAT-NPs can reduce demineralization of tooth hydroxyapatite at acidic pH. EPS, exopolysaccharides.