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

He’s being recognized for his work to better understand enzyme catalysis

A plug-and-play system fine-tunes multiple targets simultaneously for secondary metabolite production in Streptomyces.

Covering: This review covers literature from 2015 to present.It is widely recognised that there is a significant gap between bacterial natural product potential and detected/described products. As suc...

Decarboxylative condensation is essential for polyketide and fatty acid biosynthesis, yet the mechanism underlying nonelongating modules without this step remains elusive. Here the authors report a co...

Proceedings of the National Academy of Sciences (PNAS), a peer reviewed journal of the National Academy of Sciences (NAS) - an authoritative source of high-impact, original research that broadly spans...

Bioactive metabolites from plant and microbial extracts hold therapeutic potential. Here, the authors combine untargeted metabolomic arrays with flow cytometry-based single cell response profiling and...

Flow cytometry has great potential for screening in translational research areas due to its deep quantification of cellular features, ability to colle…

An intratumoural vaccination chimera reprograms tumour cells into an antigen-presenting state with restored anti-tumour immunity.

Nonribosomal peptides serve as pivotal sources for drug discovery. Accurate prediction of the substrate specificity of adenylation domains in nonribosomal peptide synthetases is crucial for genome mining of nonribosomal peptides, yet current prediction methods fall short in accuracy. In this work, we analyzed 4,100 adenylation domains from documented nonribosomal peptide synthetases and found that the flavodoxin-like subdomain universally governs substrate specificity in all bacterial adenylation domains and that its phylogenetic analysis can correlate the sequences of adenylation domains and their substrate specificity. Leveraging the sequences within the flavodoxin-like subdomain, we developed a substrate specificity prediction algorithm using a protein language model, achieving 92% overall prediction accuracy for 43 frequently observed amino acids, significantly improving the prediction reliability. The efficacy of our prediction tool was validated through targeted genome mining, which led to the discovery of novel antimicrobial peptides. Our work lays a foundation to understand the sequence-to-function relationship of the bacterial adenylation domain and will facilitate the exploitation of nonribosomal peptides. NRPStransformer is available at http://www.nrpstransformer.cn.

Nature Communications - It is commonly thought that bacterial species borders tend to be fuzzy, due to frequent exchange of DNA. Here, Diop et al. quantify the patterns of gene flow between core...

The structural complexity of natural products arises from the complexity of their biosynthetic pathways and directly contributes to their biological activities. Guided by this principle, we screened 5...

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.

As part of our long-standing program evaluating the biosynthetic complexity and biomedical potential of natural products from marine microbes, our attention was drawn to culture extracts from a Verruc...