ArticleACS chemical biology2015
Activity-Independent Discovery of Secondary Metabolites Using Chemical Elicitation and Cheminformatic Inference.
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 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Article
- Returning to Nature for the Next Generation of Antimicrobial Therapeutics.Antibiotics (Basel, Switzerland) · 2023Review
- Elicitation for activation of the actinomycete genome's cryptic secondary metabolite gene clusters.RSC advances · 2023Review
- Bioinformatic prediction and experimental validation of RiPP recognition elements.Methods in enzymology · 2023Article
- A Glossary for Chemical Approaches towards Unlocking the Trove of Metabolic Treasures inMolecules (Basel, Switzerland) · 2021Review
- An Overview of Antimicrobial Compounds from African Edible Insects and Their Associated Microbiota.Antibiotics (Basel, Switzerland) · 2021Review
- Article
- Reporter-Guided Transposon Mutant Selection for Activation of Silent Gene Clusters in Burkholderia thailandensis.Chembiochem : a European journal of chemical biology · 2020Article
- Advances in microbial culturing conditions to activate silent biosynthetic gene clusters for novel metabolite production.Journal of industrial microbiology & biotechnology · 2019Review
- Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation.Cell chemical biology · 2019Article
- Cebulantin, a Cryptic Lanthipeptide Antibiotic Uncovered Using Bioactivity-Coupled HiTES.Angewandte Chemie (International ed. in English) · 2019Article
- New Approaches to Detect Biosynthetic Gene Clusters in the Environment.Medicines (Basel, Switzerland) · 2019Review
- Efomycins K and L From a Termite-AssociatedFrontiers in microbiology · 2019Article
- Unlocking the potential of natural products in drug discovery.Microbial biotechnology · 2019Article
- Modulation of polyketide biosynthetic pathway of the endophytic fungus,Phytochemistry letters · 2018Article
- Extending the "One Strain Many Compounds" (OSMAC) Principle to Marine Microorganisms.Marine drugs · 2018Review
- Chemical Elicitors of Antibiotic Biosynthesis in Actinomycetes.Microorganisms · 2018Review
- Concepts and Methods to Access Novel Antibiotics from Actinomycetes.Antibiotics (Basel, Switzerland) · 2018Review
- Streptomyces Differentiation in Liquid Cultures as a Trigger of Secondary Metabolism.Antibiotics (Basel, Switzerland) · 2018Review
- Symbiosis-inspired approaches to antibiotic discovery.Natural product reports · 2017Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 2 countries.
Funding
Abstract
Most existing antibiotics were discovered through screens of environmental microbes, particularly the streptomycetes, for the capacity to prevent the growth of pathogenic bacteria. This "activity-guided screening" method has been largely abandoned because it repeatedly rediscovers those compounds that are highly expressed during laboratory culture. Most of these metabolites have already been biochemically characterized. However, the sequencing of streptomycete genomes has revealed a large number of "cryptic" secondary metabolic genes that are either poorly expressed in the laboratory or that have biological activities that cannot be discovered through standard activity-guided screens. Methods that reveal these uncharacterized compounds, particularly methods that are not biased in favor of the highly expressed metabolites, would provide direct access to a large number of potentially useful biologically active small molecules. To address this need, we have devised a discovery method in which a chemical elicitor called Cl-ARC is used to elevate the expression of cryptic biosynthetic genes. We show that the resulting change in product yield permits the direct discovery of secondary metabolites without requiring knowledge of their biological activity. We used this approach to identify three rare secondary metabolites and find that two of them target eukaryotic cells and not bacterial cells. In parallel, we report the first paired use of cheminformatic inference and chemical genetic epistasis in yeast to identify the target. In this way, we demonstrate that oxohygrolidin, one of the eukaryote-active compounds we identified through activity-independent screening, targets the V1 ATPase in yeast and human cells and secondarily HSP90.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.