ArticleProceedings of the National Academy of Sciences of the United States of America2014
Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 220 papers.
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220 citing papers in PubMed, 497 citations in OpenAlex.
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- Differential membrane lipid disruption by lipopeptide antibiotics, colistin and turnercyclamycins.Nature communications · 2026Article
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- iCASRED, a scarless DNA editing tool inSynthetic and systems biotechnology · 2025Article
- Coniontins, lipopetaibiotics active against Candida auris identified from a microbial natural product fractionation library.Nature communications · 2025Article
- Discovery of acylsulfenic acid-featuring natural product sulfenicin and characterization of its biosynthesis.Nature chemistry · 2025Article
- Enabling Access to Novel Bacterial Biosynthetic Potential From ONT Draft Genomic Data.Microbial biotechnology · 2025Article
- A multi-omics reciprocal analysis for characterization of bacterial metabolism.Frontiers in molecular biosciences · 2025Article
- Peptide halogenation biochemistry: interfacing pharmaceutical deliverables with chemical innovation.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2025Review
- An Improved Transformation-Associated Recombination Cloning Approach for Direct Capturing of Natural Product Biosynthetic Gene Clusters.Microbial biotechnology · 2024Article
160 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 3 countries.
Funding
Abstract
Recent developments in next-generation sequencing technologies have brought recognition of microbial genomes as a rich resource for novel natural product discovery. However, owing to the scarcity of efficient procedures to connect genes to molecules, only a small fraction of secondary metabolomes have been investigated to date. Transformation-associated recombination (TAR) cloning takes advantage of the natural in vivo homologous recombination of Saccharomyces cerevisiae to directly capture large genomic loci. Here we report a TAR-based genetic platform that allows us to directly clone, refactor, and heterologously express a silent biosynthetic pathway to yield a new antibiotic. With this method, which involves regulatory gene remodeling, we successfully expressed a 67-kb nonribosomal peptide synthetase biosynthetic gene cluster from the marine actinomycete Saccharomonospora sp. CNQ-490 and produced the dichlorinated lipopeptide antibiotic taromycin A in the model expression host Streptomyces coelicolor. The taromycin gene cluster (tar) is highly similar to the clinically approved antibiotic daptomycin from Streptomyces roseosporus, but has notable structural differences in three amino acid residues and the lipid side chain. With the activation of the tar gene cluster and production of taromycin A, this study highlights a unique "plug-and-play" approach to efficiently gaining access to orphan pathways that may open avenues for novel natural product discoveries and drug development.
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