Integration of high-content screening and untargeted metabolomics for comprehensive functional annotation of natural product libraries
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Significance: Compound Activity Mapping provides an alternative approach to natural products drug discovery by integrating high-content biological screening and untargeted metabolomics to directly reveal the identities and biological functions of individual bioactive compounds in complex natural product libraries. This accelerated discovery pipeline addresses many of the issues that have contributed to the decline of natural products research in some areas by improving dereplication and lead prioritization strategies. The detailed structural and functional annotation offered by this tool may help to improve the integration of natural products with modern high-content, high-throughput screening and provide an additional strategy for the discovery of the next generation of natural product-inspired drug leads and chemical probes.
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The Compound Activity Mapping approach combines metabolomics measurements from traditional sample fractionation with image-based screening.
“The Compound Activity Mapping approach combines metabolomics measurements from traditional sample fractionation153 with image-based screening.”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [153]
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Cites
Control of inositol 1,4,5-trisphosphate-induced Ca2+ release by cytosolic Ca2+
Bootman, M. D., Missiaen, L., Parys, J. B., SMEDT, H. D., & Casteels, R. (1995) · Biochemical Journal · doi:10.1042/bj3060445 · Cited by 5,120 · see citing works
Natural products as sources of new drugs over the 30 years from 1981 to 2010
Newman, D. J., & Cragg, G. M. (2012) · Journal of Natural Products · doi:10.1021/np200906s · Cited by 4,687 · see citing works
Open source clustering software
de Hoon, M., Imoto, S., Nolan, J., & Miyano, S. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth078 · Cited by 3,043 · see citing works
Java Treeview—extensible visualization of microarray data
Saldanha, A. J. (2004) · Bioinformatics · doi:10.1093/bioinformatics/bth349 · Cited by 2,991 · see citing works
The evolving role of natural products in drug discovery
Koehn, F. E., & Carter, G. T. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1657 · Cited by 2,579 · see citing works
Insights into Secondary Metabolism from a Global Analysis of Prokaryotic Biosynthetic Gene Clusters
Cimermančič, P., Medema, M. H., Claesen, J., Kurita, K. L., Brown, L. C. W., Mavrommatis, K., Pati, A., Godfrey, P. A., Koehrsen, M., Clardy, J., et al. (2014) · Cell · doi:10.1016/j.cell.2014.06.034 · Cited by 984 · see citing works
Self-citationMass spectral molecular networking of living microbial colonies
Watrous, J. D., Roach, P. J., Alexandrov, T., Heath, B. S., Yang, J. Y., Kersten, R. D., van der Voort, M., Pogliano, K., Gross, H., Raaijmakers, J. M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203689109 · Cited by 974 · see citing works
Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium
Høyer-Hansen, M. H., & Jäättelä, M. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402200 · Cited by 765 · see citing works
Brefeldin A inhibits Golgi membrane-catalysed exchange of guanine nucleotide onto ARF protein
Donaldson, J. G., Finazzi, D., & Klausner, R. D. (1992) · Nature · doi:10.1038/360350a0 · Cited by 760 · see citing works
Multidimensional Drug Profiling By Automated Microscopy
Perlman, Z. E., Slack, M. D., Feng, Y., Mitchison, T. J., Wu, L. F., & Altschuler, S. J. (2004) · Science · doi:10.1126/science.1100709 · Cited by 660 · see citing works
Molecular Networking as a Dereplication Strategy
Yang, J. Y., Sanchez, L. M., Rath, C. M. B., Liu, X., Boudreau, P. D., Bruns, N., Glukhov, E., Wodtke, A., de Felício, R., Fenner, A. M., et al. (2013) · Journal of Natural Products · doi:10.1021/np400413s · Cited by 613 · see citing works
Self-citationGerwick, W. H., & Moore, B. S. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2011.12.014 · Cited by 607 · see citing works
A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases
Treiman, M., Caspersen, C. S., & Christensen, S. B. (1998) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(98)01184-5 · Cited by 594 · see citing works
Structural basis for the inhibition of the eukaryotic ribosome
de Loubresse, N. G., Prokhorova, I., Holtkamp, W., Rodnina, M., Yusupova, G., & Yusupov, M. (2014) · Nature · doi:10.1038/nature13737 · Cited by 532 · see citing works
Differential Effects of Endoplasmic Reticulum Stress-induced Autophagy on Cell Survival
Ding, W., Ni, H., Gao, W., Hou, Y., Melan, M. A., Chen, X., Stolz, D. B., Shao, Z.-M., & Yin, X. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m609267200 · Cited by 481 · see citing works
A roadmap for natural product discovery based on large-scale genomics and metabolomics
Doroghazi, J. R., Albright, J. C., Goering, A. W., Ju, K., Haines, R. R., Tchalukov, K., Labeda, D. P., Kelleher, N. L., & Metcalf, W. W. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1659 · Cited by 479 · see citing works
Heifetz, A. H., Keenan, R. W., & Elbein, A. D. (1979) · Biochemistry · doi:10.1021/bi00578a008 · Cited by 446 · see citing works
Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy
Verfaillie, T., Salazar‐Roa, M., Velasco, G., & Agostinis, P. (2010) · International Journal of Cell Biology · doi:10.1155/2010/930509 · Cited by 344 · see citing works
Rishton, G. M. (2008) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2008.02.007 · Cited by 276 · see citing works
Methods for Monitoring Endoplasmic Reticulum Stress and the Unfolded Protein Response
Afshin Samali, A., FitzGerald, U., Deegan, S., & Gupta, S. (2010) · International Journal of Cell Biology · doi:10.1155/2010/830307 · Cited by 255 · see citing works
Dereplication of Microbial Natural Products by LC-DAD-TOFMS
Nielsen, K. F., Månsson, M., Rank, C., Frisvad, J. C., & Larsen, T. O. (2011) · Journal of Natural Products · doi:10.1021/np200254t · Cited by 246 · see citing works
Duncan, K., Crüsemann, M., Lechner, A., Sarkar, A., Li, J., Ziemert, N., Wang, M., Bandeira, N., Moore, B. S., Dorrestein, P. C., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.03.010 · Cited by 200 · 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
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
Krug, D., & Müller, R. (2014) · Natural Product Reports · doi:10.1039/c3np70127a · Cited by 151 · see citing works
Krug, D., Zurek, G., Revermann, O., et al. (2008) · Applied and Environmental Microbiology · doi:10.1128/aem.02863-07 · Cited by 142 · see citing works
Pluskal, T., Uehara, T., & Yanagida, M. (2012) · Analytical Chemistry · doi:10.1021/ac3000418 · Cited by 135 · see citing works
Potterat, O., & Hamburger, M. O. (2013) · Natural Product Reports · doi:10.1039/c3np20094a · Cited by 130 · see citing works
Wong, W. R., Oliver, A. G., & Linington, R. G. (2012) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.09.014 · Cited by 105 · see citing works
Self-citationHoffmann, T., Krug, D., Hüttel, S., & Müller, R. (2014) · Analytical Chemistry · doi:10.1021/ac502805w · Cited by 104 · see citing works
Coibamide A Induces mTOR-Independent Autophagy and Cell Death in Human Glioblastoma Cells
Hau, A. M., Greenwood, J. A., Löhr, C. V., Serrill, J., Proteau, P., Ganley, I. G., McPhail, K. L., & Ishmael, J. E. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065250 · Cited by 96 · see citing works
Schulze, C. J., Bray, W. M., Woerhmann, M. H., Stuart, J. M., Lokey, R. S., & Linington, R. G. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2012.12.007 · Cited by 91 · see citing works
Self-citationMånsson, M., Phipps, R. K., Gram, L., Munro, M. H. G., Larsen, T. O., & Nielsen, K. F. (2010) · Journal of Natural Products · doi:10.1021/np100151y · Cited by 82 · see citing works
Mechanism of action-based classification of antibiotics using high-content bacterial image analysis
Peach, K. C., Bray, W. M., Winslow, D., et al. (2013) · Molecular BioSystems · doi:10.1039/c3mb70027e · Cited by 71 · see citing works
Ibrahim, A., Yang, L., Johnston, C. W., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206376109 · Cited by 67 · see citing works
Navarro, G., Cheng, A. T.-A., Peach, K. C., Bray, W. M., Bernan, V. S., Yildiz, F. H., & Linington, R. G. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01781-13 · Cited by 64 · see citing works
Self-citationLarge-scale cytological profiling for functional analysis of bioactive compounds
Woehrmann, M. H., Bray, W. M., Durbin, J. K., Nisam, S. C., Michael, A. K., Glassey, E., Stuart, J. M., & Lokey, R. S. (2013) · Molecular BioSystems · doi:10.1039/c3mb70245f · Cited by 62 · see citing works
Self-citationWassermann, A. M., Lounkine, E., Urbán, L., Whitebread, S., Chen, S., Hughes, K., Guo, H., Kutlina, E., Fekete, A., Klumpp, M., et al. (2014) · ACS Chemical Biology · doi:10.1021/cb5001839 · Cited by 44 · see citing works
Fluostatins C∼E, Novel Members of the Fluostatin Family Produced by Streptomyces Strain Acta 1383
Baur, S., Niehaus, J., Karagouni, A. D., et al. (2006) · The Journal of Antibiotics · doi:10.1038/ja.2006.41 · Cited by 43 · see citing works
Discovery of antitumor agents from natural sources
Suffness, M., & Douros, J. D. (1981) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(81)90349-7 · Cited by 10 · see citing works
Pharmacokinetics and metabolism of rosaramicin in humans
Lin, C., Chung, M., Gural, R. P., et al. (1984) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.26.4.522 · Cited by 10 · see citing works
The garden of antimicrobial delights
DAVIES, J. E. (2010) · F1000 Biology Reports · doi:10.3410/b2-26 · Cited by 8 · see citing works
Primary and secondary prophylaxis of gastric variceal bleeding
Kochar, R., & Dupont, A. W. (2010) · F1000 Medicine Reports · doi:10.3410/m2-26 · Cited by 6 · see citing works
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Vitale, G. A., Geibel, C., Minda, V., Wang, M., Aron, A. T., & Petras, D. (2024) · Natural Product Reports · doi:10.1039/d3np00050h · Cited by 66 · see citing works
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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
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- Authors
- Kurita, K. L., Glassey, E., & Linington, R. G.
- Affiliations
- University of California, Santa Cruz (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-09-14
- Volume
- 112
- Issue
- 39
- Pages
- 11999-12004
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4593099
- OpenAlex
- W1854781589
- Cited by
- 156
- References
- 43
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 12 · 2023: 14 · 2022: 15 · 2021: 15 · 2020: 10 · 2019: 15 · 2018: 16 · 2017: 13 · 2016: 24
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (TW006634)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Keywords
- natural product discovery, high-content screening, untargeted metabolomics, bioactive metabolites, HeLa cells, natural extracts, endoplasmic reticulum stress, bioassay-guided fractionation, lead selection
- MeSH terms
- Biological Products, HeLa Cells, Humans, Image Processing, Computer-Assisted, Databases as Topic, Metabolomics, Drug Discovery, Data Curation
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