Targeting Streptococcus mutans Antigen I/II To Inhibit Dual-Species Biofilms with Candida albicans.

We employed structure-based drug design to target the V-region of Streptococcus mutans antigen I/II (VAgI/II) and identified inhibitors of S. mutans (SM) - C. albicans (CA) dual-species biofilms. The lead compound, SN195, inhibited SM single-species biofilms and SM-CA dual-species biofilms at IC50 values of 49.9 and 23.6 μM, respectively, without affecting the planktonic growth of either microbe. SN195 at 100 μM did not affect the growth of the tested oral commensals. The X-ray cocrystal structure of SN195 bound to VAgI/II revealed crucial interactions in the vicinity of the conserved Ca2+ ion in the binding pocket. Structure activity relationship studies resulted in the development of more potent dual-species biofilm inhibitors, 1b and 1j, with IC50 values of 12.9 μM and 0.41 μM, respectively. In a dual-species gnotobiotic rat caries model coinfected with SM and CA, treatment with SN195, 1b, or 1j significantly reduced buccal and sulcal caries scores compared to infected and untreated control rats.