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

We designed and synthesized analogues
of a previously identified
biofilm inhibitor IIIC5 to improve solubility, retain
inhibitory activities, and to facilitate encapsulation into pH-responsive
hydrogel microparticles. The optimized lead compound HA5 showed improved solubility of 120.09 μg/mL, inhibited Streptococcus mutans biofilm with an IC50 value of 6.42 μM, and did not affect the growth of oral commensal
species up to a 15-fold higher concentration. The cocrystal structure
of HA5 with GtfB catalytic domain determined at 2.35
Å resolution revealed its active site interactions. The ability
of HA5 to inhibit S. mutans Gtfs and to reduce glucan production has been demonstrated. The
hydrogel-encapsulated biofilm inhibitor (HEBI), generated
by encapsulating HA5 in hydrogel, selectively inhibited S. mutans biofilms like HA5. Treatment
of S. mutans-infected rats with HA5 or HEBI resulted in a significant reduction
in buccal, sulcal, and proximal dental caries compared to untreated,
infected rats.