Mining of the biosynthetic potential of archaea reveals diverse anti-archaeal lanthipeptides

Abstract 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.