Biochemometrics for Natural Products Research: Comparison of Data Analysis Approaches and Application to Identification of Bioactive Compounds
Open accessAbstract
A central challenge of natural products research is assigning bioactive compounds from complex mixtures. The gold standard approach to address this challenge, bioassay-guided fractionation, is often biased toward abundant, rather than bioactive, mixture components. This study evaluated the combination of bioassay-guided fractionation with untargeted metabolite profiling to improve active component identification early in the fractionation process. Key to this methodology was statistical modeling of the integrated biological and chemical data sets (biochemometric analysis). Three data analysis approaches for biochemometric analysis were compared, namely, partial least-squares loading vectors, S-plots, and the selectivity ratio. Extracts from the endophytic fungi Alternaria sp. and Pyrenochaeta sp. with antimicrobial activity against Staphylococcus aureus served as test cases. Biochemometric analysis incorporating the selectivity ratio performed best in identifying bioactive ions from these extracts early in the fractionation process, yielding altersetin (3, MIC 0.23 μg/mL) and macrosphelide A (4, MIC 75 μg/mL) as antibacterial constituents from Alternaria sp. and Pyrenochaeta sp., respectively. This study demonstrates the potential of biochemometrics coupled with bioassay-guided fractionation to identify bioactive mixture components. A benefit of this approach is the ability to integrate multiple stages of fractionation and bioassay data into a single analysis.
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Cites
National Committee for Clinical Laboratory Standards
Bruck, E. (1980) · PEDIATRICS · doi:10.1542/peds.65.1.187 · Cited by 14,736 · see citing works
Pluskal, T., Castillo, S., Villar‐Briones, A., & Orešič, M. (2010) · BMC Bioinformatics · doi:10.1186/1471-2105-11-395 · Cited by 3,852 · see citing works
The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine
Tu, Y. (2011) · Nature Medicine · doi:10.1038/nm.2471 · Cited by 1,397 · see citing works
Wiklund, S., Johansson, E., Sjöström, L., Mellerowicz, E. J., Edlund, U. G., Shockcor, J. P., Gottfries, J., Möritz, T., & Trygg, J. (2007) · Analytical Chemistry · doi:10.1021/ac0713510 · Cited by 1,234 · see citing works
Multivariate data analysis in pharmaceutics: A tutorial review
Rajalahti, T., & Kvalheim, O. M. (2011) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2011.02.019 · Cited by 770 · see citing works
Self-citationThe discovery of the vinca alkaloids—chemotherapeutic agents against cancer
NOBLE, R. L. (1990) · Biochemistry and Cell Biology · doi:10.1139/o90-197 · Cited by 388 · see citing works
Camptothecin and Taxol: Historic Achievements in Natural Products Research
Oberlies, N. H., & Kroll, D. J. (2004) · Journal of Natural Products · doi:10.1021/np030498t · Cited by 355 · see citing works
Self-citationBiomarker discovery in mass spectral profiles by means of selectivity ratio plot
Rajalahti, T., Arneberg, R., Berven, F. S., Myhr, K., Ulvik, R. J., & Kvalheim, O. M. (2008) · Chemometrics and Intelligent Laboratory Systems · doi:10.1016/j.chemolab.2008.08.004 · Cited by 277 · see citing works
Self-citationCamptothecin and taxol: from discovery to clinic
Wall, M. E., & Wani, M. C. (1996) · Journal of Ethnopharmacology · doi:10.1016/0378-8741(95)01367-9 · Cited by 268 · see citing works
Inducible NorA-mediated multidrug resistance in Staphylococcus aureus
Kaatz, G. W., & Seo, S. M. (1995) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.39.12.2650 · Cited by 268 · see citing works
Rajalahti, T., Arneberg, R., Kroksveen, A. C., Berle, M., Myhr, K., & Kvalheim, O. M. (2009) · Analytical Chemistry · doi:10.1021/ac802514y · Cited by 226 · see citing works
Self-citationNMR Metabolomics to Revisit the Tobacco Mosaic Virus Infection in Nicotiana tabacum Leaves
Choi, Y. H., Kim, H. K., Linthorst, H. J. M., et al. (2006) · Journal of Natural Products · doi:10.1021/np050535b · Cited by 190 · see citing works
A Unifying Review of Bioassay-Guided Fractionation, Effect-Directed Analysis and Related Techniques
Weller, M. G. (2012) · Sensors · doi:10.3390/s120709181 · Cited by 187 · see citing works
Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products
Hou, Y., Braun, D. R., Michel, C. R., Klassen, J. L., Adnani, N., Wyche, T. P., & Bugni, T. S. (2012) · Analytical Chemistry · doi:10.1021/ac202623g · Cited by 185 · see citing works
Interpretation of latent-variable regression models
Kvalheim, O. M., & Karstang, T. V. (1989) · Chemometrics and Intelligent Laboratory Systems · doi:10.1016/0169-7439(89)80110-8 · Cited by 184 · see citing works
Self-citationMetabolomics for bioactivity assessment of natural products
Yuliana, N. D., Khatib, A., Choi, Y. H., & Verpoorte, R. (2010) · Phytotherapy Research · doi:10.1002/ptr.3258 · Cited by 179 · see citing works
El‐Elimat, T., Figueroa, M., Ehrmann, B. M., et al. (2013) · Journal of Natural Products · doi:10.1021/np4004307 · Cited by 177 · see citing works
Technological advances in high-throughput screening
Fernandes, P. B. (1998) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(98)80089-6 · Cited by 170 · see citing works
Kleigrewe, K., Almaliti, J., Tian, I. Y., Kinnel, R. B., Korobeynikov, A., Monroe, E. A., Duggan, B. M., Marzo, V. D., Sherman, D. H., Dorrestein, P. C., et al. (2015) · Journal of Natural Products · doi:10.1021/acs.jnatprod.5b00301 · Cited by 158 · see citing works
VanderMolen, K. M., Raja, H. A., El‐Elimat, T., et al. (2013) · AMB Express · doi:10.1186/2191-0855-3-71 · Cited by 153 · see citing works
Self-citationJunio, H. A., Sy‐Cordero, A. A., Ettefagh, K. A., Burns, J. T., Micko, K. T., Graf, T. N., Richter, S. J., Cannon, R. E., Oberlies, N. H., & Cech, N. B. (2011) · Journal of Natural Products · doi:10.1021/np200336g · Cited by 152 · see citing works
Self-citationFigueroa, M., Jarmusch, A. K., Raja, H. A., El‐Elimat, T., Kavanaugh, J. S., Horswill, A. R., Cooks, R. G., Cech, N. B., & Oberlies, N. H. (2014) · Journal of Natural Products · doi:10.1021/np5000704 · Cited by 151 · see citing works
Self-citationCortina, N. S., Krug, D., Plaza, A., et al. (2011) · Angewandte Chemie International Edition · doi:10.1002/anie.201106305 · Cited by 120 · see citing works
Hellwig, V., Grothe, T., Mayer‐Bartschmid, A., et al. (2002) · The Journal of Antibiotics · doi:10.7164/antibiotics.55.881 · Cited by 113 · see citing works
Flavonolignans from Aspergillus iizukae, a Fungal Endophyte of Milk Thistle (Silybum marianum)
El‐Elimat, T., Raja, H. A., Graf, T. N., et al. (2014) · Journal of Natural Products · doi:10.1021/np400955q · Cited by 101 · see citing works
Self-citationSearching for signals in the noise: metabolomics in chemical ecology
Prince, E. K., & Pohnert, G. (2009) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-009-3162-5 · Cited by 89 · see citing works
Unbiased evaluation of bioactive secondary metabolites in complex matrices
Inui, T., Wang, Y., Pro, S. M., Franzblau, S. G., & Pauli, G. F. (2012) · Fitoterapia · doi:10.1016/j.fitote.2012.06.012 · Cited by 85 · see citing works
The utility of metabolomics in natural product and biomarker characterization
Cox, D. G., Oh, J., Keasling, A. W., Colson, K., & Hamann, M. T. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.08.007 · Cited by 84 · see citing works
Takamatsu, S., Kim, Y.-P., HAYASHI, M., et al. (1996) · The Journal of Antibiotics · doi:10.7164/antibiotics.49.95 · Cited by 76 · see citing works
Greensporones: Resorcylic Acid Lactones from an Aquatic Halenospora sp.
El‐Elimat, T., Raja, H. A., Day, C. S., et al. (2014) · Journal of Natural Products · doi:10.1021/np500497r · Cited by 73 · see citing works
Self-citationMetabolomics-Driven Discovery of a Prenylated Isatin Antibiotic Produced byStreptomycesSpecies MBT28
Wu, C., Du, C., Gubbens, J., Choi, Y. H., & van Wezel, G. P. (2015) · Journal of Natural Products · doi:10.1021/acs.jnatprod.5b00276 · Cited by 71 · see citing works
Tan, N., Tao, Y., Pan, J., et al. (2008) · Chemistry of Natural Compounds · doi:10.1007/s10600-008-9046-7 · Cited by 69 · see citing works
Sidebottom, A. M., Johnson, A. R., Karty, J. A., Trader, D. J., & Carlson, E. E. (2013) · ACS Chemical Biology · doi:10.1021/cb4002798 · Cited by 64 · see citing works
Recipe for Uncovering the Bioactive Components in Herbal Medicine
Chau, F.-T., Chan, H. Y., Cheung, C.-Y., et al. (2009) · Analytical Chemistry · doi:10.1021/ac900731z · Cited by 62 · see citing works
Martens, H. A., Bruun, S. W., Adt, I., et al. (2006) · Journal of Chemometrics · doi:10.1002/cem.1015 · Cited by 56 · see citing works
13C NMR Metabolomics: INADEQUATE Network Analysis
Clendinen, C. S., Pasquel, C., Ajredini, R., et al. (2015) · Analytical Chemistry · doi:10.1021/acs.analchem.5b00867 · Cited by 54 · see citing works
Kvalheim, O. M., Chan, H. Y., Benzie, I. F. F., et al. (2011) · Chemometrics and Intelligent Laboratory Systems · doi:10.1016/j.chemolab.2011.02.002 · Cited by 54 · see citing works
Self-citationJunio, H. A., Todd, D. A., Ettefagh, K. A., Ehrmann, B. M., Kavanaugh, J. S., Horswill, A. R., & Cech, N. B. (2013) · Journal of Chromatography B · doi:10.1016/j.jchromb.2013.04.019 · Cited by 42 · see citing works
Self-citationShang, N., Saleem, A., Musallam, L., Walshe‐Roussel, B., Badawi, A. F., Cuerrier, A., Arnason, J. T., & Haddad, P. S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0135721 · Cited by 41 · see citing works
Qiu, F., Cai, G., Jaki, B. U., et al. (2013) · Journal of Natural Products · doi:10.1021/np3007809 · Cited by 37 · see citing works
Raja, H. A., El‐Elimat, T., Oberlies, N. H., et al. (2015) · Mycologia · doi:10.3852/15-013 · Cited by 34 · see citing works
Self-citationRaja, H. A., Kaur, A., El‐Elimat, T., et al. (2015) · Mycology: An International Journal on Fungal Biology · doi:10.1080/21501203.2015.1009186 · Cited by 33 · see citing works
Self-citationCancer Chemopreventive Agents Discovered by Activity-Guided Fractionation: A Review
Kinghorn, A. D., Fong, H. H. S., Farnsworth, N. R., et al. (1998) · Current Organic Chemistry · doi:10.2174/1385272802666220130001926 · Cited by 29 · see citing works
Identification of bioactive metabolites against adenosine A1 receptor using NMR-based metabolomics
Ali, K., Iqbal, M., Yuliana, N. D., et al. (2013) · Metabolomics · doi:10.1007/s11306-013-0498-9 · Cited by 26 · see citing works
Kulakowski, D., Wu, S., Balick, M. J., & Kennelly, E. J. (2014) · Journal of Chromatography A · doi:10.1016/j.chroma.2014.08.049 · Cited by 25 · see citing works
Okada, T., Afendi, F. M., Katoh, A., Hirai, A. M., & Kanaya, S. (2012) · Springer eBooks · doi:10.1007/978-3-642-29974-2_18 · Cited by 11 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- [1]1. Kinghorn, A. D.; Fong, H. H. S.; Farnsworth, N. R.; Mehta, R. G.; Moon, R. C.; Moriarty, R. M.;Pezzuto, J. M. Curr. Org. Chem. 1998, 2, 597-612
- [2]2. Wall, M. E.; Wani, M. C. J. Ethnopharmacol. 1996, 51, 239-253 DOI: 10.1016/0378- 8741(95)01367-9 · DOI
- [7]7. Prince, E. K.; Pohnert, G. Anal. Bioanal. Chem. 2010, 396, 193-197 DOI: 10.1007/s00216- 009-3162-5 · DOI
- [17]17. Okada, T.; Afendi, F. M.; Katoh, A.; Hirai, A.; Kanaya, S. In Biotechnology for Medicinal Plants; Chandra, S.;Lata, H.; Varma, A., Eds.; Springer-Verlag: Berlin, 2013; pp 413-438.
- [22]22. Ali, K.; Iqbal, M.; Yuliana, N. D.; Lee, Y. J.; Park, S.; Han, S.; Lee, J. W.; Lee, H. S.; Verpoorte, R.;Choi, Y. H. Metabolomics 2013, 9, 778-785 DOI: 10.1007/s11306-013- 0498-9 · DOI
Cited by
Sorted by citations
Nothias, L.-F., Nothias-Esposito, M., da Silva, R., Wang, M., Protsyuk, I., Zhang, Z., Sarvepalli, A., Leyssen, P., Touboul, D., Costa, J., et al. (2018) · Journal of Natural Products · doi:10.1021/acs.jnatprod.7b00737 · Cited by 433 · see citing works
Chemometric-Guided Approaches for Profiling and Authenticating Botanical Materials
Abraham, E. J., & Kellogg, J. J. (2021) · Frontiers in Nutrition · doi:10.3389/fnut.2021.780228 · Cited by 64 · see citing works
Self-citationInteraction Metabolomics to Discover Synergists in Natural Product Mixtures
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. (2023) · Journal of Natural Products · doi:10.1021/acs.jnatprod.2c00518 · Cited by 37 · see citing works
Self-citationApplication of predictive modeling tools for the identification of Ocimum spp. herbal products
Abraham, E. J., Chamberlain, S. J., Perera, W. H., Jordan, R. T., & Kellogg, J. J. (2025) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-025-05735-0 · Cited by 2 · see citing works
“A 2 uL injection was used for all samples [21, 22].”
Self-citation
- Authors
- Kellogg, J. J., Todd, D. A., Egan, J. M., Raja, H. A., Oberlies, N. H., Kvalheim, O. M., & Cech, N. B.
- Affiliations
- University of North Carolina at Greensboro (US)
- University of Bergen (NO)
- Corresponding author
- Cech, Nadja B.
- ORCID
- Venue
- Journal of Natural Products
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-02-03
- Volume
- 79
- Issue
- 2
- Pages
- 376-386
- ISSN
- 0163-3864 (ISSN-L)
- 1520-6025
- PMC
- PMC5135737
- OpenAlex
- W2346462946
- Cited by
- 189
- References
- 46
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 25 · 2023: 15 · 2022: 18 · 2021: 12 · 2020: 21 · 2019: 25 · 2018: 14 · 2017: 11 · 2016: 8
- FWCI
- 15.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Natural Products (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- NC Digital Online Collection of Knowledge and Scholarship (The University of North Carolina at Greensboro) (submittedVersion)
- Funders
- National Center for Complementary and Integrative Health (1R01 AT006860)
- North Carolina Biotechnology Center (2011-BRG-1206)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Chemistry › Analytical Chemistry › Chromatography in Natural Products
- Keywords
- bioassay-guided fractionation, untargeted metabolomics, bioactive compound identification, selectivity ratio, endophytic fungi, Alternaria, Pyrenochaeta, antimicrobial activity, Staphylococcus aureus, natural product mixtures
- MeSH terms
- Alternaria, Anti-Bacterial Agents, Biological Products, Heterocyclic Compounds, Microbial Sensitivity Tests, Staphylococcus aureus, Molecular Structure
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