Hydrogel-Encapsulated Biofilm Inhibitors Abrogate the Cariogenic Activity of

Area of Science:

• Microbiology
• Materials Science
• Biochemistry

Background:

• Streptococcus mutans biofilms are a primary cause of dental caries.
• Previous biofilm inhibitors like IIIC5 lacked optimal solubility and delivery methods.
• Developing targeted inhibitors with improved properties is crucial for effective caries prevention.

Purpose of the Study:

• To design and synthesize novel analogues of IIIC5 with enhanced solubility and biofilm inhibitory activity.
• To facilitate the encapsulation of the lead compound into pH-responsive hydrogel microparticles for targeted delivery.
• To evaluate the efficacy of the optimized compound and its hydrogel formulation in preclinical models of dental caries.

Main Methods:

• Synthesis and characterization of HA5, an optimized analogue of IIIC5.
• Determination of HA5 solubility and Streptococcus mutans biofilm inhibition (IC50).
• Cocrystallography of HA5 with GtfB catalytic domain to elucidate active site interactions.
• Encapsulation of HA5 into pH-responsive hydrogel microparticles (HEBI).
• In vivo assessment of HA5 and HEBI in a rat dental caries model.

Main Results:

• The optimized compound HA5 exhibited improved solubility (120.09 μg/mL) and potent inhibition of Streptococcus mutans biofilms (IC50 = 6.42 μM).
• HA5 demonstrated selectivity, not affecting oral commensal species growth at therapeutically relevant concentrations.
• Cocrystal structure revealed HA5's interaction with the GtfB active site, confirming its mechanism of inhibiting glucan production.
• Hydrogel-encapsulated biofilm inhibitor (HEBI) maintained selective inhibition of S. mutans biofilms.
• Both HA5 and HEBI significantly reduced dental caries in Streptococcus mutans-infected rats.

Conclusions:

• HA5 represents a promising, highly soluble, and selective inhibitor of Streptococcus mutans biofilms.
• Hydrogel encapsulation (HEBI) provides a viable strategy for targeted delivery and sustained release of the inhibitor.
• HA5 and HEBI demonstrate significant potential for the prevention and treatment of dental caries.