Metabolic Fingerprints from the Human Oral Microbiome Reveal a Vast Knowledge Gap of Secreted Small Peptidic Molecules

Metabolomics is the ultimate tool for studies of microbial functions under any specific set of environmental conditions (D. S. Wishart, Nat Rev Drug Discov 45:473–484, 2016, https://doi.org/10.1038/nrd.2016.32 ). This is a great advance over studying genes alone, which only inform about metabolic potential. Approximately 25,000 compounds have been chemically characterized thus far; however, the richness of metabolites such as SMs has been estimated to be as high as 1 × 10 30 in the biosphere (K. Garber, Nat Biotechnol 33:228–231, 2015, https://doi.org/10.1038/nbt.3161 ). Our classical, one-at-a-time activity-guided approach to compound identification continues to find the same known compounds and is also incredibly tedious, which represents a major bottleneck for global SM identification. These challenges have prompted new developments of databases and analysis tools that provide putative classifications of SMs by mass spectral alignments to already characterized tandem mass spectrometry spectra and databases containing structural information (e.g., PubChem and AntiMarin). In this study, we assessed secreted peptidic SMs (PSMs) from 27 oral bacterial isolates and a complex oral in vitro biofilm community of >100 species by using the Global Natural Products Social molecular Networking and the DEREPLICATOR infrastructures, which are methodologies that allow automated and putative annotation of PSMs. These approaches enabled the identification of an untapped resource of PSMs from oral bacteria showing species-unique patterns of secretion with putative matches to known bioactive compounds.