Extracellular Proteins Orchestrate *Streptococcus mutans* Virulence, Biofilm Formation, and Extra-Oral Pathogenicity

Despite advances, dental caries remains a pervasive global health challenge, primarily driven by Streptococcus mutans thriving in dysbiotic plaque biofilms. These biofilms are acidogenic, aciduric, and therapeutically recalcitrant, making them difficult to eradicate. Current antimicrobial strategies often promote resistance and can harm commensal flora. While acidogenesis and extracellular polysaccharide (EPS) synthesis are known virulence factors, a deeper understanding of the extracellular protein network is crucial to develop targeted interventions that address the complex mechanisms linking carbohydrate metabolism to adhesion, matrix integrity, and interspecies communication, especially given the link to infective endocarditis and cardiovascular complications.

This review synthesizes accumulating evidence on the biological roles of extracellular proteins in Streptococcus mutans, focusing on their contribution to cariogenic fitness and extra-oral pathogenicity. Researchers systematically analyzed literature concerning major surface-anchored and secreted proteins and peptides. The scope included adhesins, glucan-binding proteins, collagen-binding proteins (Cnm/Cbm), the LPXTG display machinery, autolysin-mediated eDNA release, protease control of pheromone maturation, glucosyltransferases, peptide pheromones, and secreted bacteriocins/mutacins. The review aimed to integrate emerging concepts on how these factors contribute to biofilm formation, microenvironment creation, and community restructuring.

A coordinated network of extracellular proteins serves as the operational interface linking carbohydrate metabolism to key virulence traits in S. mutans. These proteins are critical for adhesion, shaping biofilm matrix architecture, mediating quorum-guided behaviors, and facilitating ecological competition. The review highlights how these factors build composite matrices composed of glucans, proteins, and eDNA, which in turn create diffusion-limited acidic microenvironments conducive to caries development. Regulatory layers, such as matrix-retained signaling and the interplay between the competence-stimulating peptide (CSP) and ComX-inducing peptide (XIP) circuits, were emphasized for their role in coupling competence and bacteriocin programs to community restructuring. Enzymes like SMU_833/RgpI were identified as potential modulators of glucan-eDNA interactions.

Crucially, Cnm/Cbm-positive S. mutans lineages were found to expand tissue tropism, contributing significantly to extra-oral diseases, including infective endocarditis and cardiovascular complications. This underscores the systemic impact of these specific extracellular proteins beyond oral health.