Molecular Regulation of Virulence and Dental Biofilm Formation in <i>Streptococcus mutans</i> : Unravelling the Crosstalk Between the <i>VicRK</i> and <i>LiaSR</i> Two‐Component Systems

Streptococcus mutans is one of the primary causes of dental caries and is often found in persistent endodontic infections, primarily due to its ability to form acidogenic, aciduric and therapeutically recalcitrant biofilms. The VicRK and LiaSR two-component signal transduction systems (TCS) are particularly important regulators of virulence, envelope integrity and stress response. This paper will provide an updated synthesis of the evidence, at the molecular, genetic and systems levels, regarding the architecture, regulation and integration of VicRK and LiaSR in the control of S. mutans pathogenicity. VicRK helps synthesise essential molecules for biofilm formation and reduces the negative impact of environmental stress on microbes. At the same time, LiaSR responds to antimicrobial peptides, oxidative stress, detergents and root canal irrigants by activating membrane repair and protective stress pathways. Structural, transcriptomic and proteomic studies now indicate extensive regulatory overlap, including overlapping promoter targets, cross-phosphorylation and coordinate regulation of autolysins, cell wall biosynthetic enzymes and extracellular DNA (eDNA) release. These systems all work together as part of the signalling. The ability of S. mutans to survive different pHs, oxidative bursts, lack of nutrients and chemical disinfection in and outside the mouth. According to mutant, knockout and multi-omics studies, these TCSs are critical for biofilm formation, EPS structures, antimicrobial tolerance and interspecies interactions, including synergistic virulence in mixed-species biofilms. As interest in anti-virulence therapeutics grows, drug targets VicRK and LiaSR have emerged. Potential candidates for the selective disruption of TCS signalling that are unlikely to induce resistance include small-molecule inhibitors, marine-derived bioactive compounds and computationally designed ligands. The review also highlights translational gaps and stresses the need for advanced delivery platforms, clinical validation and sustainable production of natural inhibitors. By integrating knowledge of the mechanisms underlying TCS-mediated virulence with available strategies to address it, this review offers a comprehensive overview of this topic.