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Abstract Actinobacteria are a large and diverse group of bacteria that are known to produce a wide range of secondary metabolites, many of which have important biological activities, including antibiotics, anti-cancer agents, and immunosuppressants. The biosynthesis of these compounds is often highly regulated with many natural products (NPs) being produced at very low levels in laboratory settings. Environmental factors, such as small molecule elicitors, can induce the production of secondary metabolites. Specifically, they can increase titers of known NPs as well as enabling discovery of novel NPs typically produced at undetectable levels. These elicitors can be NPs, including antibiotics or hormones, or synthetic compounds. In recent years, there has been a growing interest in the use of small molecule elicitors to induce the production of secondary metabolites from actinobacteria, especially for the discovery of NPs from “silent” biosynthetic gene clusters. This review aims to highlight classes of molecules that induce secondary metabolite production in actinobacteria and to describe the potential mechanisms of induction. One-Sentence SummaryThis review describes chemical elicitors of actinobacteria natural products described to date and the proposed mechanisms of induction.
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Recent advances in hapalindole-type cyanobacterial alkaloids: biosynthesis, synthesis, and biological activity
Covering: 1984 up to the end of 2020 Hapalindoles, fischerindoles, ambiguines and welwitindolinones are all members of a class of indole alkaloid natural products that have been isolated from the Stigonematales order of cyanobacteria. These compounds possess a polycyclic ring system, unique functional groups and various stereo- and regiochemical isomers. Since their initial isolation in 1984, they have been explored as potential therapeutics due to their wide variety of biological activities. Although numerous groups have pursued total syntheses of these densely functionalized structures, hapalindole biosynthesis has only recently been unveiled. Several groups have uncovered a wide range of novel enzymes that catalyze formation and tailoring of the hapalindole-type metabolites. In this article, we provide an overview of these natural products, their biological activities, highlight general synthetic routes, and provide an extensive review on the surprising biosynthetic processes leading to these structurally diverse metabolites.
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- Award ID(s):
- 1700982
- PAR ID:
- 10233734
- Date Published:
- Journal Name:
- Natural Product Reports
- ISSN:
- 0265-0568
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract IntroductionFungi biosynthesize chemically diverse secondary metabolites with a wide range of biological activities. Natural product scientists have increasingly turned towards bioinformatics approaches, combining metabolomics and genomics to target secondary metabolites and their biosynthetic machinery. We recently applied an integrated metabologenomics workflow to 110 fungi and identified more than 230 high-confidence linkages between metabolites and their biosynthetic pathways. ObjectivesTo prioritize the discovery of bioactive natural products and their biosynthetic pathways from these hundreds of high-confidence linkages, we developed a bioactivity-driven metabologenomics workflow combining quantitative chemical information, antiproliferative bioactivity data, and genome sequences. MethodsThe 110 fungi from our metabologenomics study were tested against multiple cancer cell lines to identify which strains produced antiproliferative natural products. Three strains were selected for further study, fractionated using flash chromatography, and subjected to an additional round of bioactivity testing and mass spectral analysis. Data were overlaid using biochemometrics analysis to predict active constituents early in the fractionation process following which their biosynthetic pathways were identified using metabologenomics. ResultsWe isolated three new-to-nature stemphone analogs, 19-acetylstemphones G (1), B (2) and E (3), that demonstrated antiproliferative activity ranging from 3 to 5 µM against human melanoma (MDA-MB-435) and ovarian cancer (OVACR3) cells. We proposed a rational biosynthetic pathway for these compounds, highlighting the potential of using bioactivity as a filter for the analysis of integrated—Omics datasets. ConclusionsThis work demonstrates how the incorporation of biochemometrics as a third dimension into the metabologenomics workflow can identify bioactive metabolites and link them to their biosynthetic machinery.more » « less
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D1NP00007A
