ArticleACS synthetic biology2019
Atolypenes, Tricyclic Bacterial Sesterterpenes Discovered Using a Multiplexed In Vitro Cas9-TAR Gene Cluster Refactoring Approach.
Article in ACS synthetic biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Discovery and Biosynthetic Characterization of Darumycins Expand the Chemical Space of Sesterterpene Antibiotics.JACS Au · 2026Article
- Advances in large DNA fragment assembly for microbial cell factory engineering.Quantitative biology (Beijing, China) · 2026Review
- Resistance-CONKAT-seq Guided Discovery of a ClpP Active Natural Product from a Soil Metagenome.ACS chemical biology · 2026Article
- Mode of action guided metagenomic natural product discovery reveals convergent evolution of a ClpP-targeting motif.Nature communications · 2026Article
- Synthetic Biology Strategies for Activating Cryptic BGCs inACS omega · 2026Review
- A Rapid and Cost-Effective Pipeline to Identify and Capture BGCs From Bacterial Draft Genomes.Bio-protocol · 2025Article
- The Evolutionary History and Modern Diversity of Triterpenoid Cyclases.Molecular biology and evolution · 2025Article
- The evolutionary history and modern diversity of triterpenoid cyclases.bioRxiv : the preprint server for biology · 2025Article
- Enabling Access to Novel Bacterial Biosynthetic Potential From ONT Draft Genomic Data.Microbial biotechnology · 2025Article
- CRISETR: an efficient technology for multiplexed refactoring of biosynthetic gene clusters.Nucleic acids research · 2024Article
- A flexible, modular and versatile functional part assembly toolkit for gene cluster engineering inSynthetic and systems biotechnology · 2024Article
- Discovery and biosynthesis of bacterial drimane-type sesquiterpenoids fromBeilstein journal of organic chemistry · 2024Article
- Actinomycetes as Producers of Biologically Active Terpenoids: Current Trends and Patents.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Article
- Parallelized gene cluster editing illuminates mechanisms of epoxyketone proteasome inhibitor biosynthesis.Nucleic acids research · 2023Article
- The Potential Use of Fungal Co-Culture Strategy for Discovery of New Secondary Metabolites.Microorganisms · 2023Review
- Multiplexed Promoter Engineering for Improving Thaxtomin A Production in HeterologousLife (Basel, Switzerland) · 2022Article
- Silent Genes: Antimicrobial Resistance and Antibiotic Production.Polish journal of microbiology · 2021Article
- Looking Back toAntibiotics (Basel, Switzerland) · 2021Review
- Marinoterpins A-C: Rare Linear Merosesterterpenoids from Marine-Derived Actinomycete Bacteria of the Family Streptomycetaceae.The Journal of organic chemistry · 2021Article
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Authors and funding
6 authors.
Funding
Abstract
Most natural product biosynthetic gene clusters identified in bacterial genomic and metagenomic sequencing efforts are silent under laboratory growth conditions. Here, we describe a scalable biosynthetic gene cluster activation method wherein the gene clusters are disassembled at interoperonic regions in vitro using CRISPR/Cas9 and then reassembled with PCR-amplified, short DNAs, carrying synthetic promoters, using transformation assisted recombination (TAR) in yeast. This simple, cost-effective, and scalable method allows for the simultaneous generation of combinatorial libraries of refactored gene clusters, eliminating the need to understand the transcriptional hierarchy of the silent genes. In two test cases, this in vitro disassembly-TAR reassembly method was used to create collections of promoter-replaced gene clusters that were tested in parallel to identify versions that enabled secondary metabolite production. Activation of the atolypene ( ato) gene cluster led to the characterization of two unprecedented bacterial cyclic sesterterpenes, atolypene A (1) and B (2), which are moderately cytotoxic to human cancer cell lines. This streamlined in vitro disassembly- in vivo reassembly method offers a simplified approach for silent gene cluster refactoring that should facilitate the discovery of natural products from silent gene clusters cloned from either metagenomes or cultured bacteria.
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