Decoding the Chemical Language of Ribosomally Synthesized and Post‐Translationally Modified Peptides from the Untapped Archaea Domain

Abstract Chemical communication is crucial in ecosystems with complex microbial communities. However, the difficulties inherent to the cultivation of archaea have led to a limited understanding of their chemical language, especially regarding the structure diversity and function of secondary metabolites (SMs). Our in‐depth exploration into the biosynthetic potential of archaea has unveiled the previously unexplored biosynthetic capabilities and chemical diversity of archaeal ribosomally synthesized and post‐translationally modified peptides (RiPPs). Through the first application of heterologous expression in archaeal SM discovery, we have identified 24 lanthipeptides, including a distinctive type featuring diamino‐dicarboxylic termini. It highlights the uniqueness of archaeal biosynthetic pathways and significantly expands the chemical landscape of archaeal SMs. Additionally, archaeal lanthipeptides demonstrate antagonistic activity against haloarchaea, mediating the unique biotic interaction in the halophilic niche. They showcase a new ecological role of RiPPs in enhancing the host's motility by inducing the rod‐shaped cell morphology and upregulating the archaellin gene expression, facilitating the archaeal interaction with abiotic environments. These discoveries broaden our understanding of archaeal chemical language and provide promising prospects for future exploration of SM‐mediated interaction.