Interaction Metabolomics to Discover Synergists in Natural Product Mixtures
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High Resolution Image Download MS PowerPoint Slide Mass spectrometry metabolomics has become increasingly popular as an integral aspect of studies to identify active compounds from natural product mixtures. Classical metabolomics data analysis approaches do not consider the possibility that interactions (such as synergy) could occur between mixture components. With this study, we developed “interaction metabolomics” to overcome this limitation. The innovation of interaction metabolomics is the inclusion of compound interaction terms (CITs), which are calculated as the product of the intensities of each pair of features (detected ions) in the data matrix. Herein, we tested the utility of interaction metabolomics by spiking known concentrations of an antimicrobial compound (berberine) and a synergist (piperine) into a set of inactive matrices. We measured the antimicrobial activity for each of the resulting mixtures against Staphylococcus aureus and analyzed the mixtures with liquid chromatography coupled to high-resolution mass spectrometry. When the data set was processed without CITs (classical metabolomics), statistical analysis yielded a pattern of false positives. However, interaction metabolomics correctly identified berberine and piperine as the compounds responsible for the synergistic activity. To further validate the interaction metabolomics approach, we prepared mixtures from extracts of goldenseal ( Hydrastis canadensis ) and habañero pepper ( Capsicum chinense ) and correctly correlated synergistic activity of these mixtures to the combined action of berberine and several capsaicinoids. Our results demonstrate the utility of a conceptually new approach for identifying synergists in mixtures that may be useful for applications in natural products research and other research areas that require comprehensive mixture analysis.
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Caesar et al. approached this challenge by the deviation from the expected bioactivity of a known bioactive compound, and demonstrated validation of several synergistic compounds, but the approach requires a priori knowledge of a known active molecule.
“Caesar et al.154 approached this challenge by the deviation from the expected bioactivity of a known bioactive compound. The authors demonstrated the validation of several synergistic compounds, however, this approach requires a priori knowledge of a known active molecule.”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [154]
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Interaction Metabolomics to Uncover Synergists in Natural Product Mixtures - DATASETS
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Cited by
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- Authors
- Vidar, W. S., Baumeister, T. U. H., Caesar, L. K., Kellogg, J. J., Todd, D. A., Linington, R. G., M. Kvalheim, O., & Cech, N. B.
- Affiliations
- University of North Carolina at Greensboro (US)
- Simon Fraser University (CA)
- James Madison University (US)
- Pennsylvania State University (US)
- Department of Chemistry, University of Bergen, Bergen 5020, Norway
- Corresponding author
- Cech, Nadja B.
- ORCID
- Venue
- Journal of Natural Products
- Publisher
- American Chemical Society (ACS)
- Published
- 2023-04-13
- Volume
- 86
- Issue
- 4
- Pages
- 655-671
- ISSN
- 0163-3864 (ISSN-L)
- 1520-6025
- PMC
- PMC10152448
- OpenAlex
- W4365442818
- Cited by
- 37
- References
- 44
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 12 · 2023: 1
- FWCI
- 3.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Natural Products (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- NC Digital Online Collection of Knowledge and Scholarship (The University of North Carolina at Greensboro) (submittedVersion)
- ScholarSphere (Penn State Libraries) (submittedVersion, cc-by)
- Funders
- National Center for Complementary and Integrative Health (R15 AT010191, U41 AT008178)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Complementary and alternative medicine › Traditional Chinese Medicine Analysis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- synergistic activity, natural product mixtures, berberine, piperine, antimicrobial activity, Staphylococcus aureus, goldenseal, Hydrastis canadensis, habanero pepper, Capsicum chinense, capsaicinoids, mixture analysis
- MeSH terms
- Alkaloids, Anti-Infective Agents, Berberine, Biological Products, Piperidines, Benzodioxoles, Polyunsaturated Alkamides, Metabolomics
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