Decoding the chemical language of RiPPs from the untapped Archaea domain

Chemical communication is crucial in ecosystems with complex microbial assemblages. However, due to archaeal cultivation challenges, our understanding of the structure diversity and function of secondary metabolites (SMs) within archaeal communities is limited compared to the extensively studied and well-documented bacterial counterparts. Our comprehensive investigation into the biosynthetic potential of archaea, combined with metabolic analyses and the first report of heterologous expression in archaea, has unveiled the previously unexplored biosynthetic capabilities and chemical diversity of archaeal ribosomally synthesized and post-translationally modified peptide (RiPP). We have identified twenty-four new lanthipeptides of RiPPs exhibiting unique chemical characteristics, including a novel subfamily featuring an unexplored type with diamino-dicarboxylic (DADC) termini, largely expanding the chemical landscape of archaeal SMs. This sheds light on the chemical novelty of archaeal metabolites and emphasizes their potential as an untapped resource for natural product discovery. Additionally, archaeal lanthipeptides demonstrate specific antagonistic activity against haloarchaea, mediating the unique biotic interaction in the halophilic niche. Furthermore, they showcased a unique ecological role in enhancing the host's motility by inducing the rod-shaped cell morphology and upregulating the archaellum gene flgA1, 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. Overall design: To investigate the function of lanthipeptide biosynthetic gene clusters (BGCs) in the motility activation assay, we collected the cell cultures of the corresponding heterologous expression strains with empty plasmid, BGC cib2 or BGC pel.