Abstract
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.
Data availability
All data supporting this study are provided in the main text and supplementary materials. Raw subgingival metagenomic sequencing data are available in NCBI BioProject PRJNA1295854, and raw multispecies biofilm metagenomic sequencing data are available in NCBI BioProject PRJNA1142934 and PRJNA1311577.
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Acknowledgements
We thank Erin Rudolph, Hyijoo Kang, Nicole Berezyuk, Caroline Hoffmann, Adam Lebowitz, Leeba Woodrow, Caroline Nicolais, and Andrew Khoury for their technical support in this study. This study was funded by Natural Products Canada, Proof of Concept Program. The funder had no role in the design, data collection, data analysis, or reporting of this study.
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A.B. and M.G. conceived and designed the study. A.B., Y.B., C.M., M.C., Y.K.C., C.N., M.O., M.X., D.W., and S.Z. developed methods and performed experiments and/or generated data. A.B., M.C., and S.Z. analyzed data and prepared figures. A.B. and M.G. acquired funding, supervised the work, and administered the project (with support from CS). A.B. and M.G. wrote the first draft of the manuscript. A.B., M.G., J.M., L.S., and T.M. reviewed and edited the manuscript. All authors reviewed and approved the final manuscript.
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A.B. and M.G. are co-founders of Ostia Sciences Inc. They are inventors on patents related to phosphorylated lantibiotics and S. salivarius SALI-10 (USA: 18/837439; Europe: EP23752199.2A). They are also inventors on a provisional patent application related to sorbitol-mediated enhancement of phosphorylated lantibiotic production (United States Provisional Application No. 63/765,057). Y.B C.M., Y.K.C., and M.C. are employees at Ostia Sciences Inc. All other authors declare they have no competing interests.
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Barbour, A., Bendayan, Y., Marks, C. et al. Phosphorylated lantibiotics-producing commensals integrate into the human oral microbiome to suppress pathogens and promote microbiome homeostasis. npj Biofilms Microbiomes (2026). https://doi.org/10.1038/s41522-026-00976-y
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DOI: https://doi.org/10.1038/s41522-026-00976-y