Coumarin-Mediated Inhibition of Diadenylate Cyclase Correlates with Impaired Biofilm Formation in Streptococcus mutans.

Streptococcus mutans diadenylate cyclase (SmDAC) catalyzes the cyclization of two ATP molecules into cyclic di-AMP, a second messenger that regulates many cellular processes including biofilm formation. Aided by structure-based drug design and subsequent structure-activity relationship studies, we identified a coumarin chemotype as low-micromolar inhibitors of SmDAC. Optimized lead compounds inhibited both biofilm formation and planktonic growth of S. mutans. Biofilm inhibition marginally exceeded growth inhibition at tested doses, indicating relative selectivity toward biofilm inhibition. Additionally, the lead inhibitor did not significantly affect the growth and biofilm of representative commensal streptococci in a mixed-species community consisting of S. mutans, S. gordonii, and S. sanguinis at 10 μM, though this selectivity was lower when tested in single-species growth and biofilm conditions. Overall, this study demonstrates that the inhibition of S. mutans' DAC and biofilm by small molecules is a potential strategy for the treatment and prevention of dental caries.