Synergistic action of specialized metabolites from divergent biosynthesis in the human oral microbiome

Despite extensive efforts, our understanding of the virulence factors contributing to oral biofilm formation-a hallmark of dental caries-remains incomplete. We present evidence that the specialized metabolism of the oral microbiome is a critical yet underexplored factor in oral biofilm formation. Through microbiome analysis, we identified a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) encoding biosynthetic gene cluster that correlates with dental caries and is widely represented in oral pathogens, including Streptococcus mutans. This gene cluster produces two major mutanoclumpin metabolites, MC-584 and MC-586, which feature molecular scaffolds differing in a C-C macrocyclic linkage. Both metabolites synergistically promote robust biofilm formation of S. mutans through a rare dual-metabolite mode of action. Further, each metabolite binds uniquely to the S. mutans cell surface, resulting in distinct multicellular morphologies. The biosynthesis of mutanoclumpins employs a unique chemical logic that produces two major products, rare within PKS-NRPS assembly lines. This study underscores the importance of characterizing genes implicated in human diseases through microbiome analysis and lays the foundation for exploring strategies to inhibit streptococci-induced dental caries.