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Dental caries, a chronic biofilm\u2010associated disease primarily driven by the AMR pathogen <jats:italic>Streptococcus mutans<\/jats:italic>, results in enamel demineralization and significant oral health challenges. This study explores the anticariogenic mechanism of marine\u2010derived cyclo(<jats:sc>l<\/jats:sc>\u2010leucyl\u2010<jats:sc>l<\/jats:sc>\u2010prolyl) (CLP), a biomolecule known to inhibit key virulence factors of <jats:italic>S. mutans<\/jats:italic> UA159. LC\u2013MS\/MS proteomic analysis revealed 30 and 71 significantly regulated proteins following 12 and 24\u00a0h of CLP treatment, respectively. Protein\u2013protein interaction and gene ontology analyses demonstrated that CLP downregulates critical virulence proteins related to <jats:sc>d<\/jats:sc>\u2010alanylation of lipoteichoic acid (LTA), glucan synthesis, acid production and acid tolerance, while upregulating proteins associated with translation, DNA repair and protein metabolism. KEGG pathway analysis highlighted the involvement of downregulated proteins in key metabolic pathways, including <jats:sc>d<\/jats:sc>\u2010alanine metabolism, starch and sucrose metabolism, glycolysis and branched\u2010chain amino acid metabolism. Given the pivotal role of <jats:sc>d<\/jats:sc>\u2010alanine metabolism in modulating interconnected virulence pathways, a comparative analysis of in vitro virulence assays\u2014including cell adherence, biofilm formation, acid production and cell surface charge\u2014alongside proteomic data signify that CLP specifically targets the <jats:sc>d<\/jats:sc>\u2010alanylation of LTA. This hypothesis was further validated by LTA and <jats:sc>d<\/jats:sc>\u2010alanine quantification assays, which confirmed a significant reduction in <jats:sc>d<\/jats:sc>\u2010alanine content within LTA after CLP treatment, leading to a marked attenuation of <jats:italic>S. mutans<\/jats:italic> cariogenic virulence. Additionally, qPCR and molecular docking analyses corroborated that CLP disrupts <jats:italic>S. mutans<\/jats:italic> virulence by interfering with the <jats:sc>d<\/jats:sc>\u2010alanylation of LTA. These findings highlight CLP's potential as a novel therapeutic agent for combating dental cariogenesis by targeting <jats:italic>S. mutans<\/jats:italic> virulence, offering a promising avenue for the development of advanced anticariogenic therapies.<\/jats:p>","DOI":"10.1111\/omi.70000","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T02:10:01Z","timestamp":1750299001000},"page":"202-222","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Marine\u2010Derived Cyclo(<scp>l<\/scp>\u2010Leucyl\u2010<scp>l<\/scp>\u2010Prolyl) Targets <scp>d<\/scp>\u2010Alanylation of Lipoteichoic Acid to Combat <i>Streptococcus mutans<\/i> UA159 Mediated Dental Cariogenesis"],"prefix":"10.1111","volume":"40","author":[{"given":"Ravichellam","family":"Sangavi","sequence":"first","affiliation":[{"name":"Department of Biotechnology Science Campus Alagappa University  Karaikudi 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