Decoding the chemical language of RiPPs from the untapped Archaea domain

AbstractChemical 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 or specialized metabolites (SMs). 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 peptides (RiPPs). 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 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.Abstract Figure