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

antiSMASH is widely used for biosynthetic gene cluster (BGC) detection and annotation, but its standard workflow is poorly suited to large metagenomic assemblies, where massive contig counts create severe runtime bottlenecks and complicate downstream result exploration. We present metaSMASH, a re-engineered fork of antiSMASH for metagenome-scale BGC analysis. metaSMASH preserves the original antiSMASH detection and annotation logic while introducing streaming, memory-bounded execution, record-level parallelisation, optional output filtering, and an interactive dashboard for large result sets. Across 25 benchmark metagenome datasets, metaSMASH reproduced identical BGC detection results while dramatically reducing computational cost. Relative to the default antiSMASH configuration, metaSMASH was a geometric-mean 38x faster. It also outperformed an ad hoc chunked antiSMASH workflow: in the default configuration it achieved a geometric-mean 2.9x speed-up and 1.7x lower peak memory, and with extended-analysis modules enabled it was 2.7x faster and used 3.1x less memory while completing all datasets, whereas the ad hoc workflow ran out of memory on the two largest assemblies. By substantially reducing the computational burden of large-scale metagenome analysis without sacrificing result equivalence, metaSMASH makes routine mining of assembled metagenomes more practical and provides a scalable foundation for natural product discovery from complex microbial communities. ### Competing Interest Statement The authors have declared no competing interest. German Center for Infection Research, TTU Novel Antibiotics 09.716 Volkswagen Foundation, 0072511-00

Abstract. Bacterial secondary metabolites are a major source of therapeutics and play key roles in microbial ecology. These compounds are encoded by biosyn

AbstractBackground. Soil ecosystems have long been recognised as hotspots of microbial diversity, but most estimates of their microbial and functional comp

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.

We are excited to launch a naming competition inspired by the recent preprint "Phylogenetic distance and structural diversity directing a reclassification of glycopeptide antibiotics" (https://www.bio...

The Ziemert lab is interested in the evolution and distribution of bacterial secondary metabolites. These bioactive compounds are especially important in human medicine as the chemical scaffolds are t...

Bacterial biosynthetic gene clusters (BGCs) drive the production of diverse bioactive specialized metabolites regulated by transcription factors (TFs) in response to environmental signals. In this met...

als Wissenschaftlerinnen und Wissenschaftler in Deutschland sind wir in großer Sorge. Die Klima­krise und weitere Umweltkrisen (Biodiversitätsverlust, Überlastung biogeochemischer Stoffkreisläu­fe ......

Streptomyces bacteria make diverse specialised metabolites that form the basis of ~55% of clinically used antibiotics. Despite this, only 3% of their encoded specialised metabolites have been matched ...