Microbes produce diverse secondary metabolites (SMs) such as signaling molecules and antimicrobials that meditate microbe-microbe interaction. Archaea, the third domain of life, are a large and diverse group of microbes that not only exist in extreme environments but are abundantly distributed throughout nature. However, our understanding of archaeal secondary metabolites lags far behind our knowledge of those in bacteria and eukarya. In particular, the metabolic origin of antagonistic interactions which shape the archaeal community remains elusive. Here, we analyze 7,157 de-replicated archaeal genomes to investigate the biosynthetic potential of archaeal SMs systematically, revealing 5,496 biosynthetic gene clusters (BGCs). Up to 2,079 BGCs encoding highly diverse ribosomally synthesized and post-translationally modified peptides (RiPPs) are widely distributed across the Archaea domain. Guided by genome mining, we discover three new lanthipeptides with diverse ring topologies from a halophilic archaeon of class Haloarchaea. Of these there lanthipeptides, a representative exhibited anti-archaeal activities against closely-related halophilic archaea, potentially mediating the archaeal antagonistic interactions. These discoveries of the widespread archaeal ribosomal peptide SMs are expected to stimulate the experimental study of poorly characterized archaeal chemical biology and highlight the potential of archaea as a new source of bioactive SMs.

Lactic acid bacteria (LAB) produce various bioactive secondary metabolites (SMs), which endow LAB with a protective role for the host. However, the biosynthetic potentials of LAB-derived SMs remain elusive, particularly in their diversity, abundance, and distribution in the human microbiome. To gain an insight into the biosynthetic capacity of LAB, we analyzed the biosynthetic gene clusters (BGCs) from 31,977 LAB genomes and 748 human microbiome metagenomes, identifying 130,051 BGCs. The found BGCs were clustered into 2,849 gene cluster families (GCFs), most of which are species-specific, niche-specific, and uncharacterized yet. We found that most LAB BGCs encoded bacteriocins with pervasive antagonistic activities predicted by machine learning models, potentially playing protective roles in the human microbiome. Class II bacteriocins, the most abundant LAB SMs, are particularly enriched and predominant in vaginal microbiomes. Together with experimental validation, our metagenomic and metatranscriptomic analysis showed that class II bacteriocins with antagonistic potential might regulate microbial communities in the vagina, thereby contributing to homeostasis. These discoveries of the diverse and prevalent antagonistic SMs are expected to stimulate the mechanism study of LABs' protective roles in the host and highlight the potential of LAB as a new source of antibacterial SMs.