Hydrogel-Encapsulated Biofilm Inhibitors Abrogate the Cariogenic Activity of Streptococcus mutans

We designed and synthesized analoguesof a previously identifiedbiofilm inhibitor IIIC5 to improve solubility, retaininhibitory activities, and to facilitate encapsulation into pH-responsivehydrogel microparticles. The optimized lead compound HA5 showed improved solubility of 120.09 mu g/mL, inhibited Streptococcus mutans biofilm with an IC50 value of 6.42 mu M, and did not affect the growth of oral commensalspecies up to a 15-fold higher concentration. The cocrystal structureof HA5 with GtfB catalytic domain determined at 2.35 angstrom resolution revealed its active site interactions. The abilityof HA5 to inhibit S. mutans Gtfs and to reduce glucan production has been demonstrated. Thehydrogel-encapsulated biofilm inhibitor (HEBI), generatedby encapsulating HA5 in hydrogel, selectively inhibited S. mutans biofilms like HA5. Treatmentof S. mutans-infected rats with HA5 or HEBI resulted in a significant reductionin buccal, sulcal, and proximal dental caries compared to untreated,infected rats.