Natural Sciences

Natural products in drug discovery: advances and opportunities

Written by Mamie M. Arndt
  • 1.

    Atanasov, A. G. et al. Discovery and resupply of pharmacologically active plant-derived natural products: a review. Biotechnol. Adv. 33, 1582–1614 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 2.

    Harvey, A. L., Edrada-Ebel, R. & Quinn, R. J. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14, 111–129 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 3.

    Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 4.

    Waltenberger, B., Mocan, A., Šmejkal, K., Heiss, E. H. E. H. & Atanasov, A. A. G. A. G. Natural products to counteract the epidemic of cardiovascular and metabolic disorders. Molecules 21, 807 (2016).

    PubMed Central 
    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 5.

    Tintore, M., Vidal-Jordana, A. & Sastre-Garriga, J. Treatment of multiple sclerosis — success from bench to bedside. Nat. Rev. Neurol. 15, 53–58 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 6.

    Feher, M. & Schmidt, J. M. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci. 43, 218–227 (2003).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 7.

    Barnes, E. C., Kumar, R. & Davis, R. A. The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery. Nat. Prod. Rep. 33, 372–381 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 8.

    Li, J. W.-H. & Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 9.

    Clardy, J. & Walsh, C. Lessons from natural molecules. Nature 432, 829–837 (2004).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 10.

    Lawson, A. D. G., MacCoss, M. & Heer, J. P. Importance of rigidity in designing small molecule drugs to tackle protein–protein interactions (PPIs) through stabilization of desired conformers. J. Med. Chem. 61, 4283–4289 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 11.

    Doak, B. C., Over, B., Giordanetto, F. & Kihlberg, J. Oral druggable space beyond the rule of 5: insights from drugs and clinical candidates. Chem. Biol. 21, 1115–1142 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 12.

    Shultz, M. D. Two decades under the influence of the rule of five and the changing properties of approved oral drugs. J. Med. Chem. 62, 1701–1714 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 13.

    Lachance, H., Wetzel, S., Kumar, K. & Waldmann, H. Charting, navigating, and populating natural product chemical space for drug discovery. J. Med. Chem. 55, 5989–6001 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 14.

    Henrich, C. J. & Beutler, J. A. Matching the power of high throughput screening to the chemical diversity of natural products. Nat. Prod. Rep. 30, 1284 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 15.

    Cragg, G. M., Schepartz, S. A., Suffness, M. & Grever, M. R. The taxol supply crisis. New NCI policies for handling the large-scale production of novel natural product anticancer and anti-HIV agents. J. Nat. Prod. 56, 1657–1668 (1993).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 16.

    Harrison, C. Patenting natural products just got harder. Nat. Biotechnol. 32, 403–404 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 17.

    Burton, G. & Evans-Illidge, E. A. Emerging R and D law: the Nagoya Protocol and its implications for researchers. ACS Chem. Biol. 9, 588–591 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 18.

    Heffernan, O. Why a landmark treaty to stop ocean biopiracy could stymie research. Nature 580, 20–22 (2020).

    PubMed 
    Article 

    Google Scholar
     

  • 19.

    Corson, T. W. & Crews, C. M. Molecular understanding and modern application of traditional medicines: triumphs and trials. Cell 130, 769–774 (2007).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 20.

    Moffat, J. G., Vincent, F., Lee, J. A., Eder, J. & Prunotto, M. Opportunities and challenges in phenotypic drug discovery: an industry perspective. Nat. Rev. Drug Discov. 16, 531–543 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 21.

    Shi, Y., Inoue, H., Wu, J. C. & Yamanaka, S. Induced pluripotent stem cell technology: a decade of progress. Nat. Rev. Drug Discov. 16, 115–130 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 22.

    Fellmann, C., Gowen, B. G., Lin, P.-C., Doudna, J. A. & Corn, J. E. Cornerstones of CRISPR–Cas in drug discovery and therapy. Nat. Rev. Drug Discov. 16, 89–100 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 23.

    Schirle, M. & Jenkins, J. L. Identifying compound efficacy targets in phenotypic drug discovery. Drug Discov. Today 21, 82–89 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 24.

    Wagenaar, M. M. Pre-fractionated microbial samples-the second generation natural products library at Wyeth. Molecules 13, 1406–1426 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 25.

    Wolfender, J.-L., Nuzillard, J.-M., van der Hooft, J. J. J., Renault, J.-H. & Bertrand, S. Accelerating metabolite identification in natural product research: toward an ideal combination of liquid chromatography–high-resolution tandem mass spectrometry and nmr profiling, in silico databases, and chemometrics. Anal. Chem. 91, 704–742 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 26.

    Stuart, K. A., Welsh, K., Walker, M. C. & Edrada-Ebel, R. A. Metabolomic tools used in marine natural product drug discovery. Expert Opin. Drug Discov. 15, 499–522 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 27.

    Allard, P.-M., Genta-Jouve, G. & Wolfender, J.-L. Deep metabolome annotation in natural products research: towards a virtuous cycle in metabolite identification. Curr. Opin. Chem. Biol. 36, 40–49 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 28.

    Allard, P.-M. et al. Pharmacognosy in the digital era: shifting to contextualized metabolomics. Curr. Opin. Biotechnol. 54, 57–64 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 29.

    Hubert, J., Nuzillard, J.-M. & Renault, J.-H. Dereplication strategies in natural product research: How many tools and methodologies behind the same concept? Phytochem. Rev. 16, 55–95 (2017).

    CAS 
    Article 

    Google Scholar
     

  • 30.

    Liu, X. & Locasale, J. W. Metabolomics: a primer. Trends Biochem. Sci. 42, 274–284 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 31.

    Eugster, P. J. et al. Ultra high pressure liquid chromatography for crude plant extract profiling. J. AOAC Int. 94, 51–70 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 32.

    Stavrianidi, A. A classification of liquid chromatography mass spectrometry techniques for evaluation of chemical composition and quality control of traditional medicines. J. Chromatogr. A 1609, 460501 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 33.

    Wolfender, J.-L., Marti, G., Thomas, A. & Bertrand, S. Current approaches and challenges for the metabolite profiling of complex natural extracts. J. Chromatogr. A 1382, 136–164 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 34.

    Tahtah, Y. et al. High-resolution PTP1B inhibition profiling combined with high-performance liquid chromatography–high-resolution mass spectrometry–solid-phase extraction–nuclear magnetic resonance spectroscopy: proof-of-concept and antidiabetic constituents in crude extract of Eremophila lucida. Fitoterapia 110, 52–58 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 35.

    Chu, C. et al. Antidiabetic constituents of Dendrobium officinale as determined by high-resolution profiling of radical scavenging and α-glucosidase and α-amylase inhibition combined with HPLC-PDA-HRMS-SPE-NMR analysis. Phytochem. Lett. 31, 47–52 (2019).

    CAS 
    Article 

    Google Scholar
     

  • 36.

    Garcia-Perez, I. et al. Identifying unknown metabolites using NMR-based metabolic profiling techniques. Nat. Protoc. 15, 2538–2567 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 37.

    Giavalisco, P. et al. High-resolution direct infusion-based mass spectrometry in combination with whole 13C metabolome isotope labeling allows unambiguous assignment of chemical sum formulas. Anal. Chem. 80, 9417–9425 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 38.

    Covington, B. C., McLean, J. A. & Bachmann, B. O. Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites. Nat. Prod. Rep. 34, 6–24 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 39.

    Fontana, A., Iturrino, L., Corens, D. & Crego, A. L. Automated open-access liquid chromatography high resolution mass spectrometry to support drug discovery projects. J. Pharm. Biomed. Anal. 178, 112908 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 40.

    Kind, T. et al. Identification of small molecules using accurate mass MS/MS search. Mass. Spectrom. Rev. 37, 513–532 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 41.

    Wang, M. et al. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat. Biotechnol. 34, 828–837 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 42.

    Yang, J. Y. et al. Molecular networking as a dereplication strategy. J. Nat. Prod. 76, 1686–1699 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 43.

    Allen, F., Greiner, R. & Wishart, D. Competitive fragmentation modeling of ESI-MS/MS spectra for putative metabolite identification. Metabolomics 11, 98–110 (2015).

    CAS 
    Article 

    Google Scholar
     

  • 44.

    Allard, P.-M. et al. Integration of molecular networking and in-silico MS/MS fragmentation for natural products dereplication. Anal. Chem. 88, 3317–3323 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 45.

    da Silva, R. R. et al. Propagating annotations of molecular networks using in silico fragmentation. PLoS Comput. Biol. 14, e1006089 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 46.

    Randazzo, G. M. et al. Prediction of retention time in reversed-phase liquid chromatography as a tool for steroid identification. Anal. Chim. Acta 916, 8–16 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 47.

    Zhou, Z., Xiong, X. & Zhu, Z.-J. MetCCS predictor: a web server for predicting collision cross-section values of metabolites in ion mobility-mass spectrometry based metabolomics. Bioinformatics 33, 2235–2237 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 48.

    Rutz, A. et al. Taxonomically informed scoring enhances confidence in natural products annotation. Front. Plant. Sci. 10, 1329 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 49.

    Guijas, C. et al. METLIN: a technology platform for identifying knowns and unknowns. Anal. Chem. 90, 3156–3164 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 50.

    Aksenov, A. A., da Silva, R., Knight, R., Lopes, N. P. & Dorrestein, P. C. Global chemical analysis of biology by mass spectrometry. Nat. Rev. Chem. 1, 0054 (2017).

    CAS 
    Article 

    Google Scholar
     

  • 51.

    Fox Ramos, A. E. et al. CANPA: computer-assisted natural products anticipation. Anal. Chem. 91, 11247–11252 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 52.

    Wolfender, J.-L., Litaudon, M., Touboul, D. & Queiroz, E. F. Innovative omics-based approaches for prioritisation and targeted isolation of natural products – new strategies for drug discovery. Nat. Prod. Rep. 36, 855–868 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 53.

    Graziani, V. et al. Metabolomic approach for a rapid identification of natural products with cytotoxic activity against human colorectal cancer cells. Sci. Rep. 8, 5309 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 54.

    Grienke, U. et al. 1H NMR-MS-based heterocovariance as a drug discovery tool for fishing bioactive compounds out of a complex mixture of structural analogues. Sci. Rep. 9, 11113 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 55.

    Aligiannis, N. et al. Heterocovariance based metabolomics as a powerful tool accelerating bioactive natural product identification. ChemistrySelect 1, 2531–2535 (2016).

    CAS 
    Article 

    Google Scholar
     

  • 56.

    Acharya, D. et al. Omics technologies to understand activation of a biosynthetic gene cluster in Micromonospora sp. WMMB235: deciphering keyicin biosynthesis. ACS Chem. Biol. 14, 1260–1270 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 57.

    Schulze, C. J. et al. ‘Function-first’ lead discovery: mode of action profiling of natural product libraries using image-based screening. Chem. Biol. 20, 285–295 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 58.

    Kurita, K. L., Glassey, E. & Linington, R. G. Integration of high-content screening and untargeted metabolomics for comprehensive functional annotation of natural product libraries. Proc. Natl Acad. Sci. USA 112, 11999–12004 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 59.

    Earl, D. C. et al. Discovery of human cell selective effector molecules using single cell multiplexed activity metabolomics. Nat. Commun. 9, 39 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 60.

    Wishart, D. S. NMR metabolomics: a look ahead. J. Magn. Reson. 306, 155–161 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 61.

    Berlinck, R. G. S. et al. Approaches for the isolation and identification of hydrophilic, light-sensitive, volatile and minor natural products. Nat. Prod. Rep. 36, 981–1004 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 62.

    Hilton, B. D. & Martin, G. E. Investigation of the experimental limits of small-sample heteronuclear 2D NMR. J. Nat. Prod. 73, 1465–1469 (2010).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 63.

    Sultan, S. et al. Evolving trends in the dereplication of natural product extracts. 3: Further lasiodiplodins from Lasiodiplodia theobromae, an endophyte from Mapania kurzii. Tetrahedron Lett. 55, 453–455 (2014).

    CAS 
    Article 

    Google Scholar
     

  • 64.

    Jones, C. G. et al. The CryoEM method MicroED as a powerful tool for small molecule structure determination. ACS Cent. Sci. 4, 1587–1592 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 65.

    Ting, C. P. et al. Use of a scaffold peptide in the biosynthesis of amino acid-derived natural products. Science 365, 280–284 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 66.

    Ganesh, T. et al. Evaluation of the tubulin-bound paclitaxel conformation: synthesis, biology, and SAR studies of C-4 to C-3′ bridged paclitaxel analogues. J. Med. Chem. 50, 713–725 (2007).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 67.

    Choules, M. P. et al. Residual complexity does impact organic chemistry and drug discovery: the case of rufomyazine and rufomycin. J. Org. Chem. 83, 6664–6672 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 68.

    Ziemert, N., Alanjary, M. & Weber, T. The evolution of genome mining in microbes – a review. Nat. Prod. Rep. 33, 988–1005 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 69.

    Viehrig, K. et al. Structure and biosynthesis of crocagins: polycyclic posttranslationally modified ribosomal peptides from Chondromyces crocatus. Angew. Chem. Int. Ed. Engl. 56, 7407–7410 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 70.

    Surup, F. et al. Crocadepsins-depsipeptides from the myxobacterium Chondromyces crocatus found by a genome mining approach. ACS Chem. Biol. 13, 267–272 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 71.

    Kayrouz, C. M., Zhang, Y., Pham, T. M. & Ju, K. S. Genome mining reveals the phosphonoalamide natural products and a new route in phosphonic acid biosynthesis. ACS Chem. Biol. 15, 1921–1929 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 72.

    Laureti, L. et al. Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens. Proc. Natl Acad. Sci. USA 108, 6258–6263 (2011).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 73.

    Weber, T. & Kim, H. U. The secondary metabolite bioinformatics portal: Computational tools to facilitate synthetic biology of secondary metabolite production. Synth. Syst. Biotechnol. 1, 69–79 (2016).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 74.

    Navarro-Muñoz, J. C. et al. A computational framework to explore large-scale biosynthetic diversity. Nat. Chem. Biol. 16, 60–68 (2020).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 75.

    Hoffmann, T. et al. Correlating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria. Nat. Commun. 9, 803 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 76.

    Helaly, S. E., Thongbai, B. & Stadler, M. Diversity of biologically active secondary metabolites from endophytic and saprotrophic fungi of the ascomycete order Xylariales. Nat. Prod. Rep. 35, 992–1014 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 77.

    Dalinova, A. et al. Isolation and bioactivity of secondary metabolites from solid culture of the fungus, Alternaria sonchi. Biomolecules 10, 81 (2020).

    CAS 
    PubMed Central 
    Article 
    PubMed 

    Google Scholar
     

  • 78.

    Zerikly, M. & Challis, G. L. Strategies for the discovery of new natural products by genome mining. ChemBioChem 10, 625–633 (2009).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 79.

    Culp, E. J. et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature 578, 582–587 (2020).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 80.

    Zhang, H., Boghigian, B. A., Armando, J. & Pfeifer, B. A. Methods and options for the heterologous production of complex natural products. Nat. Prod. Rep. 28, 125–151 (2011).

    PubMed 
    Article 

    Google Scholar
     

  • 81.

    Anyaogu, D. C. & Mortensen, U. H. Heterologous production of fungal secondary metabolites in aspergilli. Front. Microbiol. 6, 77 (2015).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 82.

    Sucipto, H., Pogorevc, D., Luxenburger, E., Wenzel, S. C. & Müller, R. Heterologous production of myxobacterial α-pyrone antibiotics in Myxococcus xanthus. Metab. Eng. 44, 160–170 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 83.

    Nora, L. C. et al. The art of vector engineering: towards the construction of next-generation genetic tools. Microb. Biotechnol. 12, 125–147 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 84.

    Bok, J. W. et al. Fungal artificial chromosomes for mining of the fungal secondary metabolome. BMC Genomics 16, 343 (2015).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 85.

    Clevenger, K. D. et al. A scalable platform to identify fungal secondary metabolites and their gene clusters. Nat. Chem. Biol. 13, 895–901 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 86.

    Mao, D., Okada, B. K., Wu, Y., Xu, F. & Seyedsayamdost, M. R. Recent advances in activating silent biosynthetic gene clusters in bacteria. Curr. Opin. Microbiol. 45, 156–163 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 87.

    Rutledge, P. J. & Challis, G. L. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat. Rev. Microbiol. 13, 509–523 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 88.

    Yamanaka, K. et al. Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc. Natl Acad. Sci. 111, 1957–1962 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 89.

    Sidda, J. D. et al. Discovery of a family of γ-aminobutyrate ureas via rational derepression of a silent bacterial gene cluster. Chem. Sci. 5, 86–89 (2014).

    CAS 
    Article 

    Google Scholar
     

  • 90.

    Wang, B., Guo, F., Dong, S.-H. & Zhao, H. Activation of silent biosynthetic gene clusters using transcription factor decoys. Nat. Chem. Biol. 15, 111–114 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 91.

    Zhang, M. M. et al. CRISPR–Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. Nat. Chem. Biol. 13, 607–609 (2017).

    CAS 
    Article 

    Google Scholar
     

  • 92.

    Culp, E. J. et al. Hidden antibiotics in actinomycetes can be identified by inactivation of gene clusters for common antibiotics. Nat. Biotechnol. 37, 1149–1154 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 93.

    Hover, B. M. et al. Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat. Microbiol. 3, 415–422 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 94.

    Chu, J. et al. Discovery of MRSA active antibiotics using primary sequence from the human microbiome. Nat. Chem. Biol. 12, 1004–1006 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 95.

    Kersten, R. D. & Weng, J.-K. Gene-guided discovery and engineering of branched cyclic peptides in plants. Proc. Natl Acad. Sci. USA 115, E10961–E10969 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 96.

    Dutertre, S. et al. Deep venomics reveals the mechanism for expanded peptide diversity in cone snail venom. Mol. Cell. Proteom. 12, 312–329 (2013).

    CAS 
    Article 

    Google Scholar
     

  • 97.

    Wilson, M. C. et al. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 506, 58–62 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 98.

    Mori, T. et al. Single-bacterial genomics validates rich and varied specialized metabolism of uncultivated Entotheonella sponge symbionts. Proc. Natl Acad. Sci. USA 115, 1718–1723 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 99.

    Rath, C. M. et al. Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743. ACS Chem. Biol. 6, 1244–1256 (2011).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 100.

    Newman, D. J. Are microbial endophytes the ‘actual’ producers of bioactive antitumor agents? Trends Cancer 4, 662–670 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 101.

    Helfrich, E. J. N. et al. Bipartite interactions, antibiotic production and biosynthetic potential of the Arabidopsis leaf microbiome. Nat. Microbiol. 3, 909–919 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 102.

    Yan, F. et al. Biosynthesis and heterologous production of vioprolides: rational biosynthetic engineering and unprecedented 4-methylazetidinecarboxylic acid formation. Angew. Chem. Int. Ed. 57, 8754–8759 (2018).

    CAS 
    Article 

    Google Scholar
     

  • 103.

    Tu, Q. et al. Genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via Red/ET recombineering. Sci. Rep. 6, 21066 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 104.

    Song, C. et al. Enhanced heterologous spinosad production from a 79-kb synthetic multioperon assembly. ACS Synth. Biol. 8, 137–147 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 105.

    Wlodek, A. et al. Diversity oriented biosynthesis via accelerated evolution of modular gene clusters. Nat. Commun. 8, 1206 (2017).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 106.

    Bozhüyük, K. A. J. et al. De novo design and engineering of non-ribosomal peptide synthetases. Nat. Chem. 10, 275–281 (2018).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 107.

    Bozhüyük, K. A. J. et al. Modification and de novo design of non-ribosomal peptide synthetases using specific assembly points within condensation domains. Nat. Chem. 11, 653–661 (2019).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 108.

    Awakawa, T. et al. Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution. Nat. Commun. 9, 3534 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 109.

    Masschelein, J. et al. A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nat. Chem. 11, 906–912 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 110.

    Kosol, S. et al. Structural basis for chain release from the enacyloxin polyketide synthase. Nat. Chem. 11, 913–923 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 111.

    Gregory, M. A. et al. Structure guided design of improved anti-proliferative rapalogs through biosynthetic medicinal chemistry. Chem. Sci. 4, 1046–1052 (2013).

    CAS 
    Article 

    Google Scholar
     

  • 112.

    Méndez, C., González-Sabín, J., Morís, F. & Salas, J. A. Expanding the chemical diversity of the antitumoral compound mithramycin by combinatorial biosynthesis and biocatalysis: the quest for mithralogs with improved therapeutic window. Planta Med. 81, 1326–1338 (2015).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 113.

    Hindra et al. Genome mining of Streptomyces mobaraensis DSM40847 as a bleomycin producer providing a biotechnology platform to engineer designer bleomycin analogues. Org. Lett. 19, 1386–1389 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 114.

    Brautaset, T. et al. Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei. Chem. Biol. 15, 1198–1206 (2008).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 115.

    Preobrazhenskaya, M. N. et al. Synthesis and study of the antifungal activity of new mono- and disubstituted derivatives of a genetically engineered polyene antibiotic 28,29-didehydronystatin A1 (S44HP). J. Antibiot. 63, 55–64 (2010).

    CAS 
    Article 

    Google Scholar
     

  • 116.

    Tevyashova, A. N. et al. Structure-antifungal activity relationships of polyene antibiotics of the amphotericin B group. Antimicrob. Agents Chemother. 57, 3815–3822 (2013).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 117.

    Lewis, K., Epstein, S., D’Onofrio, A. & Ling, L. L. Uncultured microorganisms as a source of secondary metabolites. J. Antibiot. 63, 468–476 (2010).

    CAS 
    Article 

    Google Scholar
     

  • 118.

    Schiewe, H.-J. & Zeeck, A. Cineromycins, γ-butyrolactones and ansamycins by analysis of the secondary metabolite pattern created by a single strain of Strepomyces. J. Antibiot. 52, 635–642 (1999).

    CAS 
    Article 

    Google Scholar
     

  • 119.

    Zähner, H. Some aspects of antibiotics research. Angew. Chem. Int. Ed. Engl. 16, 687–694 (1977).

    PubMed 
    Article 

    Google Scholar
     

  • 120.

    Newman, D. Screening and identification of novel biologically active natural compounds. F1000Research 6, 783 (2017).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 121.

    Hussain, A. et al. Novel bioactive molecules from Lentzea violacea strain AS 08 using one strain-many compounds (OSMAC) approach. Bioorg. Med. Chem. Lett. 27, 2579–2582 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 122.

    Hemphill, C. F. P. et al. OSMAC approach leads to new fusarielin metabolites from Fusarium tricinctum. J. Antibiot. 70, 726–732 (2017).

    CAS 
    Article 

    Google Scholar
     

  • 123.

    Vartoukian, S. R., Palmer, R. M. & Wade, W. G. Strategies for culture of ‘unculturable’ bacteria. FEMS Microbiol. Lett. 309, 1–7 (2010).

    CAS 
    PubMed 

    Google Scholar
     

  • 124.

    Moussa, M. et al. Co-culture of the fungus Fusarium tricinctum with Streptomyces lividans induces production of cryptic naphthoquinone dimers. RSC Adv. 9, 1491–1500 (2019).

    CAS 
    Article 

    Google Scholar
     

  • 125.

    Abdel-Razek, A. S., Hamed, A., Frese, M., Sewald, N. & Shaaban, M. Penicisteroid C: new polyoxygenated steroid produced by co-culturing of Streptomyces piomogenus with Aspergillus niger. Steroids 138, 21–25 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 126.

    D’Onofrio, A. et al. Siderophores from neighboring organisms promote the growth of uncultured bacteria. Chem. Biol. 17, 254–264 (2010).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 127.

    Van Arnam, E. B., Currie, C. R. & Clardy, J. Defense contracts: molecular protection in insect-microbe symbioses. Chem. Soc. Rev. 47, 1638–1651 (2018).

    PubMed 
    Article 

    Google Scholar
     

  • 128.

    Molloy, E. M. & Hertweck, C. Antimicrobial discovery inspired by ecological interactions. Curr. Opin. Microbiol. 39, 121–127 (2017).

    PubMed 
    Article 

    Google Scholar
     

  • 129.

    Tobias, N. J., Shi, Y. M. & Bode, H. B. Refining the natural product repertoire in entomopathogenic bacteria. Trends Microbiology 26, 833–840 (2018).

    CAS 
    Article 

    Google Scholar
     

  • 130.

    Imai, Y. et al. A new antibiotic selectively kills Gram-negative pathogens. Nature 576, 459–464 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 131.

    Bode, E. et al. Biosynthesis and function of simple amides in Xenorhabdus doucetiae. Environ. Microbiol. 19, 4564–4575 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 132.

    Crawford, J. M., Kontnik, R. & Clardy, J. Regulating alternative lifestyles in entomopathogenic bacteria. Curr. Biol. 20, 69–74 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 133.

    Zengler, K. et al. Cultivating the uncultured. Proc. Natl Acad. Sci. USA 99, 15681–15686 (2002).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 134.

    Nichols, D. et al. Use of ichip for high-throughput in situ cultivation of ‘uncultivable’ microbial species. Appl. Environ. Microbiol. 76, 2445–2450 (2010).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 135.

    Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455–459 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 136.

    Homma, T. et al. Dual targeting of cell wall precursors by teixobactin leads to cell lysis. Antimicrob. Agents Chemother. 60, 6510–6517 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 137.

    Pham, V. H. T. & Kim, J. Cultivation of unculturable soil bacteria. Trends Biotechnol. 30, 475–484 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 138.

    Derewacz, D. K., Covington, B. C., McLean, J. A. & Bachmann, B. O. Mapping microbial response metabolomes for induced natural product discovery. ACS Chem. Biol. 10, 1998–2006 (2015).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 139.

    Lagier, J. C. et al. Culture of previously uncultured members of the human gut microbiota by culturomics. Nat. Microbiol. 1, 16203 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 140.

    Terekhov, S. S. et al. Microfluidic droplet platform for ultrahigh-throughput single-cell screening of biodiversity. Proc. Natl Acad. Sci. USA 114, 2550–2555 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 141.

    Challinor, V. L. & Bode, H. B. Bioactive natural products from novel microbial sources. Ann. NY Acad. Sci. 1354, 82–97 (2015).

    PubMed 
    Article 

    Google Scholar
     

  • 142.

    Pidot, S. J., Coyne, S., Kloss, F. & Hertweck, C. Antibiotics from neglected bacterial sources. Int. J. Med. Microbiol. 304, 14–22 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 143.

    Lincke, T., Behnken, S., Ishida, K., Roth, M. & Hertweck, C. Closthioamide: an unprecedented polythioamide antibiotic from the strictly anaerobic bacterium Clostridium cellulolyticum. Angew. Chem. Int. Ed. 49, 2011–2013 (2010).

    CAS 
    Article 

    Google Scholar
     

  • 144.

    Haeckl, F. P. J. et al. A selective genome-guided method for environmental Burkholderia isolation. J. Ind. Microbiol. Biotechnol. 46, 345–362 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 145.

    Cross, K. L. et al. Targeted isolation and cultivation of uncultivated bacteria by reverse genomics. Nat. Biotechnol. 37, 1314–1321 (2019).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 146.

    Vlachou, P. et al. Innovative approach to sustainable marine invertebrate chemistry and a scale-up technology for open marine ecosystems. Mar. Drugs 16, 152 (2018).

    PubMed Central 
    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 147.

    Zainal-Abidin, M. H., Hayyan, M., Hayyan, A. & Jayakumar, N. S. New horizons in the extraction of bioactive compounds using deep eutectic solvents: a review. Anal. Chim. Acta 979, 1–23 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 148.

    Dai, Y., van Spronsen, J., Witkamp, G.-J., Verpoorte, R. & Choi, Y. H. Ionic liquids and deep eutectic solvents in natural products research: mixtures of solids as extraction solvents. J. Nat. Prod. 76, 2162–2173 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 149.

    Nemes, P. & Vertes, A. Ambient mass spectrometry for in vivo local analysis and in situ molecular tissue imaging. Trends Analyt. Chem. 34, 22–34 (2012).

    CAS 
    Article 

    Google Scholar
     

  • 150.

    Pasquini, C. Near infrared spectroscopy: a mature analytical technique with new perspectives–a review. Anal. Chim. Acta 1026, 8–36 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 151.

    Hutchings, M., Truman, A. & Wilkinson, B. Antibiotics: past, present and future. Curr. Opin. Microbiol. 51, 72–80 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 152.

    Rossiter, S. E., Fletcher, M. H. & Wuest, W. M. Natural products as platforms to overcome antibiotic resistance. Chem. Rev. 117, 12415–12474 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 153.

    Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 154.

    Lešnik, U. et al. Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering. Angew. Chem. Int. Ed. Engl. 54, 3937–3940 (2015).

    PubMed 
    Article 
    CAS 
    PubMed Central 

    Google Scholar
     

  • 155.

    Kling, A. et al. Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348, 1106–1112 (2015).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 156.

    Shaeer, K. M., Zmarlicka, M. T., Chahine, E. B., Piccicacco, N. & Cho, J. C. Plazomicin: a next-generation aminoglycoside. Pharmacotherapy 39, 77–93 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 157.

    Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 561, 189–194 (2018).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 158.

    Dickey, S. W., Cheung, G. Y. C. & Otto, M. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance. Nat. Rev. Drug Discov. 16, 457–471 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 159.

    Park, S. R. et al. Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat. Commun. 7, 10710 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 160.

    Mann, J. Natural products in cancer chemotherapy: past, present and future. Nat. Rev. Cancer 2, 143–148 (2002).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 161.

    Beck, A., Goetsch, L., Dumontet, C. & Corvaïa, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 162.

    Pereira, R. B. et al. Marine-derived anticancer agents: clinical benefits, innovative mechanisms, and new targets. Mar. Drugs 17 (2019).

  • 163.

    Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).

    CAS 
    PubMed 
    Article 
    PubMed Central 

    Google Scholar
     

  • 164.

    Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 165.

    Menger, L. et al. Cardiac glycosides exert anticancer effects by inducing immunogenic cell death. Sci. Transl. Med. 4, 143ra99 (2012).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 166.

    Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 167.

    Diederich, M. Natural compound inducers of immunogenic cell death. Arch. Pharm. Res. 42, 629–645 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 168.

    Radogna, F., Dicato, M. & Diederich, M. Natural modulators of the hallmarks of immunogenic cell death. Biochem. Pharmacol. 162, 55–70 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 169.

    Schmidt, B. M., Ribnicky, D. M., Lipsky, P. E. & Raskin, I. Revisiting the ancient concept of botanical therapeutics. Nat. Chem. Biol. 3, 360–366 (2007).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 170.

    Schmidt, B. et al. A natural history of botanical therapeutics. Metabolism 57, S3–S9 (2008).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 171.

    Kellogg, J. J. et al. Comparison of metabolomics approaches for evaluating the variability of complex botanical preparations: green tea (Camellia sinensis) as a case study. J. Nat. Prod. 80, 1457–1466 (2017).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 172.

    Marchesi, J. R. et al. The gut microbiota and host health: a new clinical frontier. Gut 65, 330–339 (2016).

    Article 

    Google Scholar
     

  • 173.

    Abdollahi-Roodsaz, S., Abramson, S. B. & Scher, J. U. The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat. Rev. Rheumatol. 12, 446–455 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 174.

    Lynch, S. V. & Pedersen, O. The human intestinal microbiome in health and disease. N. Engl. J. Med. 375, 2369–2379 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 175.

    Scherlach, K. & Hertweck, C. Mediators of mutualistic microbe-microbe interactions. Nat. Prod. Rep. 35, 303–308 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 176.

    Modi, S. R., Collins, J. J. & Relman, D. A. Antibiotics and the gut microbiota. J. Clin. Invest. 124, 4212–4218 (2014).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 177.

    Peterson, C. T. et al. Effects of turmeric and curcumin dietary supplementation on human gut microbiota: a double-blind, randomized, placebo-controlled pilot study. J Evid. Based Integr. Med. 23, 2515690X18790725 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 178.

    Eid, H. M. et al. Significance of microbiota in obesity and metabolic diseases and the modulatory potential by medicinal plant and food ingredients. Front. Pharmacol. 8, (2017).

  • 179.

    Valencia, P. M., Richard, M., Brock, J. & Boglioli, E. The human microbiome: opportunity or hype? Nat. Rev. Drug Discov. 16, 823–824 (2017).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 180.

    Sorokina, M. & Steinbeck, C. Review on natural products databases: Where to find data in 2020. J. Cheminform. 12, 20 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 181.

    Schneider, G. et al. Deorphaning the macromolecular targets of the natural anticancer compound doliculide. Angew. Chem. Int. Ed. 55, 12408–12411 (2016).

    CAS 
    Article 

    Google Scholar
     

  • 182.

    Palazzotto, E. & Weber, T. Omics and multi-omics approaches to study the biosynthesis of secondary metabolites in microorganisms. Curr. Opin. Microbiol. 45, 109–116 (2018).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 183.

    Dias, T., Gaudêncio, S. P. & Pereira, F. A computer-driven approach to discover natural product leads for methicillin-resistant staphylococcus aureus infection therapy. Mar. Drugs 17, 16 (2019).

    CAS 
    Article 

    Google Scholar
     

  • 184.

    Boström, J., Brown, D. G., Young, R. J. & Keserü, G. M. Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discov. 17, 709–727 (2018).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 185.

    Zhao, X. et al. A novel drug discovery strategy inspired by traditional medicine philosophies. Science 347, S38–S40 (2015).


    Google Scholar
     

  • 186.

    Liao, S. et al. Tanshinol borneol ester, a novel synthetic small molecule angiogenesis stimulator inspired by botanical formulations for angina pectoris. Br. J. Pharmacol. 176, 3143–3160 (2019).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • 187.

    Bai, Y. et al. Polygala tenuifoliaAcori tatarinowii herbal pair as an inspiration for substituted cinnamic α-asaronol esters: design, synthesis, anticonvulsant activity, and inhibition of lactate dehydrogenase study. Eur. J. Med. Chem. 183, 111650 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 188.

    Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 189.

    Wang, L. et al. Novel interactomics approach identifies ABCA1 as direct target of evodiamine, which increases macrophage cholesterol efflux. Sci. Rep. 8, 11061 (2018).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 190.

    Chang, J., Kim, Y. & Kwon, H. J. Advances in identification and validation of protein targets of natural products without chemical modification. Nat. Prod. Rep. 33, 719–730 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 191.

    Adhikari, J. & Fitzgerald, M. C. SILAC-pulse proteolysis: a mass spectrometry-based method for discovery and cross-validation in proteome-wide studies of ligand binding. J. Am. Soc. Mass. Spectrom. 25, 2073–2083 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 192.

    Gregori-Puigjane, E. et al. Identifying mechanism-of-action targets for drugs and probes. Proc. Natl Acad. Sci. USA 109, 11178–11183 (2012).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 193.

    Yñigez-Gutierrez, A. E. & Bachmann, B. O. Fixing the unfixable: the art of optimizing natural products for human medicine. J. Med. Chem. 62, 8412–8428 (2019).

    PubMed 
    PubMed Central 
    Article 
    CAS 

    Google Scholar
     

  • 194.

    Markley, J. L. & Wencewicz, T. A. Tetracycline-inactivating enzymes. Front. Microbiol. 9, 1058 (2018).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 195.

    Wu, F. et al. Chrysomycin A derivatives for the treatment of multi-drug-resistant tuberculosis. ACS Cent. Sci. 6, 928–938 (2020).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 196.

    Dayalan Naidu, S., Kostov, R. V. & Dinkova-Kostova, A. T. Transcription factors Hsf1 and Nrf2 engage in crosstalk for cytoprotection. Trends Pharmacol. Sci. 36, 6–14 (2015).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 197.

    Hayes, J. D. & Dinkova-Kostova, A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199–218 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 198.

    Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 199.

    Murphy, K. E. & Park, J. J. Can co-activation of Nrf2 and neurotrophic signaling pathway slow Alzheimer’s disease? Int. J. Mol. Sci. 18, 1168 (2017).

    PubMed Central 
    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • 200.

    Cuadrado, A. et al. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat. Rev. Drug Discov. 18, 295–317 (2019).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 201.

    Linker, R. A. et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134, 678–692 (2011).

    PubMed 
    Article 

    Google Scholar
     

  • 202.

    Singh, K. et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc. Natl Acad. Sci. USA 111, 15550–15555 (2014).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 203.

    Spencer, S. R., Wilczak, C. A. & Talalay, P. Induction of glutathione transferases and NAD(P)H:quinone reductase by fumaric acid derivatives in rodent cells and tissues. Cancer Res. 50, 7871–7875 (1990).

    CAS 
    PubMed 

    Google Scholar
     

  • 204.

    Soušek, J. et al. Alkaloids and organic acids content of eight Fumaria species. Phytochem. Anal. 10, 6–11 (1999).

    Article 

    Google Scholar
     

  • 205.

    Linker, R. A. & Haghikia, A. Dimethyl fumarate in multiple sclerosis: latest developments, evidence and place in therapy. Ther. Adv. Chronic Dis. 7, 198–207 (2016).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 206.

    Fox, R. J. et al. Efficacy and tolerability of delayed-release dimethyl fumarate in Black, Hispanic, and Asian patients with relapsing-remitting multiple sclerosis: post hoc integrated analysis of DEFINE and CONFIRM. Neurol. Ther. 6, 175–187 (2017).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 207.

    Fernández, Ó. et al. Efficacy and safety of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: an integrated analysis of DEFINE and CONFIRM. Clin. Ther. 39, 1671–1679 (2017).

    PubMed 
    Article 
    CAS 

    Google Scholar
     

  • 208.

    Zhang, Y., Talalay, P., Cho, C. G. & Posner, G. H. A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc. Natl Acad. Sci. USA 89, 2399–2403 (1992).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 209.

    Dinkova-Kostova, A. T. et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl Acad. Sci. USA 99, 11908–11913 (2002).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 210.

    Morroni, F. et al. Neuroprotective effect of sulforaphane in 6-hydroxydopamine-lesioned mouse model of Parkinson’s disease. Neurotoxicology 36, 63–71 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 211.

    Liu, Y. et al. Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington’s disease. J. Neurochem. 129, 539–547 (2014).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 212.

    Kim, H. V. et al. Amelioration of Alzheimer’s disease by neuroprotective effect of sulforaphane in animal model. Amyloid 20, 7–12 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 213.

    Zhao, J., Moore, A. N., Clifton, G. L. & Dash, P. K. Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. J. Neurosci. Res. 82, 499–506 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 214.

    Benedict, A. L. et al. Neuroprotective effects of sulforaphane after contusive spinal cord injury. J. Neurotrauma 29, 2576–2586 (2012).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 215.

    Alfieri, A. et al. Sulforaphane preconditioning of the Nrf2/HO-1 defense pathway protects the cerebral vasculature against blood-brain barrier disruption and neurological deficits in stroke. Free Radic. Biol. Med. 65, 1012–1022 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 216.

    Wu, S. et al. Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice. Behav. Brain Res. 301, 55–62 (2016).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 217.

    Li, B. et al. Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp. Neurol. 250, 239–249 (2013).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 218.

    Egner, P. A. et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev. Res. 7, 813–823 (2014).

    CAS 
    Article 

    Google Scholar
     

  • 219.

    Chen, J. G. et al. Dose-dependent detoxication of the airborne pollutant benzene in a randomized trial of broccoli sprout beverage in Qidong, China. Am. J. Clin. Nutr. 110, 675–684 (2019).

    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • 220.

    Howell, S. J. et al. Final results of the STEM trial: SFX-01 in the treatment and evaluation of ER+ Her2– metastatic breast cancer (mBC). Ann. Oncol. 30, v122 (2019).

    Article 

    Google Scholar
     

  • 221.

    Dinkova-Kostova, A. T. et al. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc. Natl Acad. Sci. USA 102, 4584–4589 (2005).

    CAS 
    PubMed 
    Article 

    Google Scholar
     

  • 222.

    Liby, K. T. & Sporn, M. B. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol. Rev. 64, 972–1003 (2012).

    CAS 
    PubMed 
    PubMed Central 
    Article 

    Google Scholar
     

  • About the author

    Mamie M. Arndt