ArticleACS chemical biology2015
Identification of Thiotetronic Acid Antibiotic Biosynthetic Pathways by Target-directed Genome Mining.
Article in ACS chemical biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 133 papers.
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Who cites it
133 citing papers in PubMed.
- Advances in large DNA fragment assembly for microbial cell factory engineering.Quantitative biology (Beijing, China) · 2026Review
- Self-resistance as a guide to discovering bioactive natural products.Current opinion in chemical biology · 2026Review
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- Exploring FabH inhibitors for antimicrobial therapy: medicinal chemistry, synthetic approaches, and SAR evaluation.Molecular diversity · 2026Review
- Discovery of Partner Protein-Dependent Graspetide Biosynthesis.ACS chemical biology · 2026Article
- Diketopiperazines with In vivo Antimalarial Activity from Sponge-derived Streptomyces sp. 13-12-16.Marine biotechnology (New York, N.Y.) · 2026Article
- ARTS-DB 2.0: an expanded database for target-directed genome mining across bacteria and fungi.Database : the journal of biological databases and curation · 2026Article
- ThiF-Like Enzyme Chemistry in Primary and Secondary Metabolism.Chembiochem : a European journal of chemical biology · 2025Review
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- Biosynthesis of antibiotics with sulfonamide and azaindane moieties.The Journal of antibiotics · 2025Review
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Genome mining reveals the biosynthetic potential of a novel Lysinibacillus zambalensis sp. nov., isolated from a hyperalkaline spring.Archives of microbiology · 2025Article
- Self-resistance-gene-guided, high-throughput automated genome mining of bioactive natural products from Streptomyces.Cell systems · 2025Article
- Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- An Improved Transformation-Associated Recombination Cloning Approach for Direct Capturing of Natural Product Biosynthetic Gene Clusters.Microbial biotechnology · 2024Article
- Primed for Discovery.Biochemistry · 2024Review
- Endophytic Streptomyces: an underexplored source with potential for novel natural drug discovery and development.Archives of microbiology · 2024Review
- Review
- Recent advances in the direct cloning of large natural product biosynthetic gene clusters.Engineering microbiology · 2023Review
73 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors.
Funding
Abstract
Recent genome sequencing efforts have led to the rapid accumulation of uncharacterized or "orphaned" secondary metabolic biosynthesis gene clusters (BGCs) in public databases. This increase in DNA-sequenced big data has given rise to significant challenges in the applied field of natural product genome mining, including (i) how to prioritize the characterization of orphan BGCs and (ii) how to rapidly connect genes to biosynthesized small molecules. Here, we show that by correlating putative antibiotic resistance genes that encode target-modified proteins with orphan BGCs, we predict the biological function of pathway specific small molecules before they have been revealed in a process we call target-directed genome mining. By querying the pan-genome of 86 Salinispora bacterial genomes for duplicated house-keeping genes colocalized with natural product BGCs, we prioritized an orphan polyketide synthase-nonribosomal peptide synthetase hybrid BGC (tlm) with a putative fatty acid synthase resistance gene. We employed a new synthetic double-stranded DNA-mediated cloning strategy based on transformation-associated recombination to efficiently capture tlm and the related ttm BGCs directly from genomic DNA and to heterologously express them in Streptomyces hosts. We show the production of a group of unusual thiotetronic acid natural products, including the well-known fatty acid synthase inhibitor thiolactomycin that was first described over 30 years ago, yet never at the genetic level in regards to biosynthesis and autoresistance. This finding not only validates the target-directed genome mining strategy for the discovery of antibiotic producing gene clusters without a priori knowledge of the molecule synthesized but also paves the way for the investigation of novel enzymology involved in thiotetronic acid natural product biosynthesis.
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