Genome mining identifies a diversity of natural product biosynthetic capacity in human respiratory strains.

species, integral to the healthy human upper respiratory tract (URT) microbiota, remain underexplored in microbial genomics for their potential to promote respiratory health and exclude pathobionts. This genomic study investigated the diversity and capacity for natural product synthesis within these species, as indicated by their biosynthetic gene clusters (BGCs). We aimed to map and quantify the BGC diversity in a contemporary collection of strains, representative of their prevalence in the respiratory microbiota, and to elucidate intra- and interspecies variation in BGC content. The outcomes of this research could reveal key factors in maintaining the ecological balance of the upper respiratory tract and identify novel antimicrobial agents targeting respiratory pathobionts. Employing an approach, we analyzed the biosynthetic potential of respiratory strains of non-diphtheriae species and their reference genomes through genome sequencing and antiSMASH6 analysis. Among 161 genomes, we identified 672 BGCs, 495 of which were unique, including polyketide synthase, non-ribosomal peptide synthetase, ribosomally synthesized and post-translationally modified peptide, and siderophore families. To understand how this biosynthetic capacity compared to other respiratory bacteria, we then downloaded genomes from eight species that are associated with the URT and conducted BGC searches. We found that despite their compact genomes, species possess a multitude of predicted BGCs, exceeding the diversity of natural product BGCs identified in multiple other respiratory bacteria. This research lays the foundation for future functional genomics studies on the role of species in the respiratory microbiome and the discovery of novel therapeutics derived from this bacterial genus.IMPORTANCEBacterial secondary metabolites, produced by enzymes encoded by biosynthetic gene clusters, are ecologically important for bacterial communication and competition in nutrient-scarce environments and are a historically rich source of antibiotics and other medications. Human-associated species, abundant in the healthy upper respiratory tract, are understudied despite evidence of their roles in promoting human health and preventing pathobiont colonization. Through genome mining of a large collection of strains isolated from the human respiratory tract and publicly available genomes of other respiratory bacteria, our study suggests that species have a high biosynthetic capacity and are predicted to harbor a wide range of biosynthetic gene cluster families. These findings substantially expand current knowledge regarding the production of secondary metabolites by human-associated species. Our study also lays the foundations for understanding how species interact in the healthy human upper respiratory tract and the potential for discovering novel biotherapeutics.