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 (V^AgI/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 V^AgI/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.