Phosphorylated lantibiotics-producing commensals integrate into the human oral microbiome to suppress pathogens and promote microbiome homeostasis.

Commensal bacteria produce antimicrobial peptides (AMPs) to maintain microbiome homeostasis, yet the traits underlying this resilience and their translation into biotherapeutics remain understudied. Phosphorylated lantibiotics (pLANs) are a recently identified class of ribosomally synthesized and post-translationally modified peptides (RiPPs), with dual antimicrobial and pro-immune activities. In this manuscript, we explore the potential of commensals' pLANs biosynthesis as a mechanism for pathogen suppression and microbiome homeostasis. Subgingival metagenomics revealed that oral health correlates with Streptococcus salivarius enrichment and an increased prevalence of streptococcal RiPP biosynthetic gene clusters. Guided by these associations, we screened 80 S. salivarius isolates, identifying a small subset producing pLANs with potent activity against Porphyromonas gingivalis, vancomycin-resistant Enterococcus faecium, and multidrug-resistant Streptococcus pneumoniae. A representative lead strain, SALI-10, exhibited robust epithelial adhesion and a sorbitol-driven metabolic adaptation that enhances pLANs expression. In human-derived dysbiotic biofilms, SALI-10 stably engrafted, suppressed periopathogens, reduced antibiotic-resistance genes, and enriched acid-buffering pathways. In a first-in-human feasibility trial, daily oral administration of SALI-10 for one week yielded increased pLANs signals, pathogen depletion, and reduced oral neutrophil counts. Ultimately, pLANs-producing S. salivarius acts as a precision commensal to restore ecological balance, defining a mechanistically grounded and microbiota-mediated strategy to prevent oral and respiratory infections.