Author summary Escherichia coli demonstrates a remarkable ability to adapt to diverse environments. This adaptability is in part connected to its ability to recombine incoming DNA in its chromosome, a...

Surprise discovery could pave the way for new treatments against drug-resistant infections.

Bacteria acquire new genes by horizontal gene transfer, typically mediated by mobile genetic elements (MGEs). While plasmids, bacteriophages, and c...

Author summary Bacterial cell division is an ancient and essential process, but our molecular understanding of this process is primarily based on studies in a select few model systems. Recent work fou...

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.