Biosynthetic gene clusters (BGCs) are sets of often heterologous genes that are genetically and functionally linked. Among eukaryotes, BGCs are mos...

Background Soil ecosystems have long been recognized as hotspots of microbial diversity, but most estimates of their complexity remain speculative, relying on limited data and extrapolation from shall...

Biosynthetic gene clusters (BGCs) are contiguous genomic regions that encode diverse, non-homologous proteins required for the production of specific natural products. Their genetic diversity underlie...

Bacteria produce natural products to adapt to their environments, with phage interactions as major ecological and evolutionary drivers. While some nat…

Abstract. The increasing prevalence of antimicrobial resistance requires efficient strategies to prioritize biosynthetic gene clusters (BGCs) that may enco

Culture-independent metagenomic approaches have proven to be effective tools for identifying previously hidden biosynthetic gene clusters (BGCs) encoding novel natural products with potential medical relevance. However, producing these compounds remains challenging as metagenomic BGCs often originate from organisms phylogenetically distant from available heterologous hosts. Lasso peptides, a subclass of ribosomally synthesized and post-translationally modified peptide (RiPP) natural products, exhibit diverse bioactivities, yet no lasso peptide has previously been discovered directly from a metagenome. Here, we report the discovery and heterologous expression of the first soil metagenome-derived lasso peptide. Expression of its biosynthetic gene cluster in Escherichia coli, followed by mass spectrometry analysis, strongly supported the predicted amino acid sequence and lasso structure of the peptide. Notably, this lasso peptide is the first to feature asparagine as the ring-forming residue at position one. Taxonomic analysis of the corresponding BGC identified an uncultivated member of the Steroidobacterales family (Gammaproteobacteria) as the closest known relative of the potential native host. These findings underscore the potential of metagenomic genome mining to reveal structurally novel RiPPs and to expand our understanding of the natural diversity of lasso peptides.

Abstract. Bacterial genomes contain thousands of biosynthetic gene clusters (BGCs) responsible for the production of structurally diverse natural products

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Background Heterologous expression in Streptomyces provides a platform for mining natural products (NPs) encoded by cryptic biosynthetic gene clusters (BGCs) of bacteria. The BGCs are first engineered...

Abstract. The increasing prevalence of antimicrobial resistance requires efficient strategies to prioritize biosynthetic gene clusters (BGCs) that may enco