Bacteria provide a rich source of natural products with potential therapeutic applications, such as novel antibiotic classes or anticancer drugs. Bioactivity-guided screening of bacterial extracts and characterization of biosynthetic pathways for drug discovery is now complemented by the availability of large (meta)genomic collections, placing researchers into the postgenomic, big-data era. The progress in next-generation sequencing and the rise of powerful computational tools provide unprecedented insights into unexplored taxa, ecological niches and ‘biosynthetic dark matter’, revealing diverse and chemically distinct natural products in previously unstudied bacteria. In this Review, we discuss such sources of new chemical entities and the implications for drug discovery with a particular focus on the strategies that have emerged in recent years to identify and access novelty.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Communications Open Access 23 March 2023
The little things that matter: how bioprospecting microbial biodiversity can build towards the realization of United Nations Sustainable Development Goals
npj Biodiversity Open Access 07 December 2022
Journal of Natural Medicines Open Access 08 November 2022
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Carter, H. E. et al. Isolation and purification of streptomycin. J. Biol. Chem. 160, 337–342 (1945).
Davies, J. & Ryan, K. S. Introducing the parvome: bioactive compounds in the microbial world. ACS Chem. Biol. 7, 252–259 (2012).
Medema, M. H. & Fischbach, M. A. Computational approaches to natural product discovery. Nat. Chem. Biol. 11, 639–648 (2015).
Blin, K. et al. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47, W81–W87 (2019).
Skinnider, M. A., Merwin, N. J., Johnston, C. W. & Magarvey, N. A. PRISM 3: expanded prediction of natural product chemical structures from microbial genomes. Nucleic Acids Res. 45, W49–W54 (2017).
Sugimoto, Y. et al. A metagenomic strategy for harnessing the chemical repertoire of the human microbiome. Science 366, 1332 (2019).
Russell, A. H. & Truman, A. W. Genome mining strategies for ribosomally synthesised and post-translationally modified peptides. Comput. Struct. Biotechnol. J. 18, 1838–1851 (2020).
van Heel, A. J. et al. BAGEL4: a user-friendly web server to thoroughly mine RiPPs and bacteriocins. Nucleic Acids Res. 46, W278–W281 (2018).
Uddin, M. A. et al. A plant endophyte Staphylococcus hominis strain MBL_AB63 produces a novel lantibiotic, homicorcin and a position one variant. Sci. Rep. 11, 11211 (2021).
Kloosterman, A. M., Shelton, K. E., van Wezel, G. P., Medema, M. H. & Mitchell, D. A. RRE-Finder: a genome-mining tool for class-independent RiPP discovery. mSystems 5, e00267 (2020).
Agrawal, P., Khater, S., Gupta, M., Sain, N. & Mohanty, D. RiPPMiner: a bioinformatics resource for deciphering chemical structures of RiPPs based on prediction of cleavage and cross-links. Nucleic Acids Res. 45, W80–W88 (2017).
Saad, H. et al. Nocathioamides, uncovered by a tunable metabologenomic approach, define a novel class of chimeric lanthipeptides. Angew. Chem. Int. Ed. 60, 16472–16479 (2021).
Tietz, J. I. et al. A new genome-mining tool redefines the lasso peptide biosynthetic landscape. Nat. Chem. Biol. 13, 470–478 (2017).
Schwalen, C. J., Hudson, G. A., Kille, B. & Mitchell, D. A. Bioinformatic expansion and discovery of thiopeptide antibiotics. J. Am. Chem. Soc. 140, 9494–9501 (2018).
Agrawal, P., Amir, S., Deepak, Barua, D. & Mohanty, D. RiPPMiner-Genome: a web resource for automated prediction of crosslinked chemical structures of RiPPs by genome mining. J. Mol. Biol. 433, 166887 (2021).
Merwin, N. J. et al. DeepRiPP integrates multiomics data to automate discovery of novel ribosomally synthesized natural products. Proc. Natl Acad. Sci. USA 117, 371–380 (2020).
de Los Santos, E. L. C. NeuRiPP: neural network identification of RiPP precursor peptides. Sci. Rep. 9, 13406 (2019).
Santos-Aberturas, J. et al. Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool. Nucleic Acids Res. 47, 4624–4637 (2019).
Russell, A. H., Vior, N. M., Hems, E. S., Lacret, R. & Truman, A. W. Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature. Chem. Sci. 12, 11769–11778 (2021).
Skinnider, M. A. et al. Genomic charting of ribosomally synthesized natural product chemical space facilitates targeted mining. Proc. Natl Acad. Sci. USA 113, E6343–E6351 (2016).
Villebro, R., Shaw, S., Blin, K. & Weber, T. Sequence-based classification of type II polyketide synthase biosynthetic gene clusters for antiSMASH. J. Ind. Microbiol. Biotechnol. 46, 469–475 (2019).
Weber, T. et al. antiSMASH 3.0 — a comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Res. 43, W237–W243 (2015).
Chevrette, M. G., Aicheler, F., Kohlbacher, O., Currie, C. R. & Medema, M. H. SANDPUMA: ensemble predictions of nonribosomal peptide chemistry reveal biosynthetic diversity across Actinobacteria. Bioinformatics 33, 3202–3210 (2017).
Stachelhaus, T., Mootz, H. D. & Marahiel, M. A. The specificity-conferring code of adenylation domains in nonribosomal peptide synthetases. Chem. Biol. 6, 493–505 (1999).
Challis, G. L., Ravel, J. & Townsend, C. A. Predictive, structure-based model of amino acid recognition by nonribosomal peptide synthetase adenylation domains. Chem. Biol. 7, 211–224 (2000).
Röttig, M. et al. NRPSpredictor2 — a web server for predicting NRPS adenylation domain specificity. Nucleic Acids Res. 39, W362–W367 (2011).
Chu, J. et al. Synthetic-bioinformatic natural product antibiotics with diverse modes of action. J. Am. Chem. Soc. 142, 14158–14168 (2020).
Wu, C., Shang, Z., Lemetre, C., Ternei, M. A. & Brady, S. F. Cadasides, calcium-dependent acidic lipopeptides from the soil metagenome that are active against multidrug-resistant bacteria. J. Am. Chem. Soc. 141, 3910–3919 (2019).
Helfrich, E. J. N. & Piel, J. Biosynthesis of polyketides by trans-AT polyketide synthases. Nat. Prod. Rep. 33, 231–316 (2016).
Nguyen, T. et al. Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection. Nat. Biotechnol. 26, 225–233 (2008).
Helfrich, E. J. N. et al. Automated structure prediction of trans-acyltransferase polyketide synthase products. Nat. Chem. Biol. 15, 813–821 (2019).
Ueoka, R. et al. Genome-based identification of a plant-associated marine bacterium as a rich natural product source. Angew. Chem. Int. Ed. 57, 14519–14523 (2018).
Helfrich, E. J. N. et al. Bipartite interactions, antibiotic production and biosynthetic potential of the Arabidopsis leaf microbiome. Nat. Microbiol. 3, 909–919 (2018).
Jahanshah, G. et al. Discovery of the cyclic lipopeptide gacamide A by genome mining and repair of the defective GacA regulator in Pseudomonas fluorescens Pf0-1. J. Nat. Prod. 82, 301–308 (2019).
Culp, E. J. et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling. Nature 578, 582–587 (2020).
Kautsar, S. A. et al. MIBiG 2.0: a repository for biosynthetic gene clusters of known function. Nucleic Acids Res. 48, D454–D458 (2020).
Blin, K., Shaw, S., Kautsar, S. A., Medema, M. H. & Weber, T. The antiSMASH database version 3: increased taxonomic coverage and new query features for modular enzymes. Nucleic Acids Res. 49, D639–D643 (2021).
Palaniappan, K. et al. IMG-ABC v.5.0: an update to the IMG/Atlas of biosynthetic gene clusters knowledgebase. Nucleic Acids Res. 48, D422–D430 (2020).
Kautsar, S. A., Blin, K., Shaw, S., Weber, T. & Medema, M. H. BiG-FAM: the biosynthetic gene cluster families database. Nucleic Acids Res. 49, D490–D497 (2021).
van Santen, J. A. et al. The Natural Products Atlas: an open access knowledge base for microbial natural products discovery. ACS Cent. Sci. 5, 1824–1833 (2019).
Banerjee, P. et al. Super Natural II — a database of natural products. Nucleic Acids Res. 43, D935–D939 (2015).
Sorokina, M. & Steinbeck, C. Review on natural products databases: where to find data in 2020. J. Cheminform 12, 20 (2020).
Clark, C. M., Costa, M. S., Sanchez, L. M. & Murphy, B. T. Coupling MALDI-TOF mass spectrometry protein and specialized metabolite analyses to rapidly discriminate bacterial function. Proc. Natl Acad. Sci. USA 115, 4981–4986 (2018).
Reher, R. et al. A convolutional neural network-based approach for the rapid annotation of molecularly diverse natural products. J. Am. Chem. Soc. 142, 4114–4120 (2020).
Bhushan, A., Egli, P. J., Peters, E. E., Freeman, M. F. & Piel, J. Genome mining- and synthetic biology-enabled production of hypermodified peptides. Nat. Chem. 11, 931–939 (2019).
Vila-Farres, X. et al. Antimicrobials inspired by nonribosomal peptide synthetase gene clusters. J. Am. Chem. Soc. 139, 1404–1407 (2017).
Johnston, C. W. et al. An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products. Nat. Commun. 6, 8421 (2015).
Kersten, R. D. et al. A mass spectrometry-guided genome mining approach for natural product peptidogenomics. Nat. Chem. Biol. 7, 794–802 (2011).
Medema, M. H. et al. Pep2Path: automated mass spectrometry-guided genome mining of peptidic natural products. PLoS Comput. Biol. 10, e1003822 (2014).
Kersten, R. D. et al. Glycogenomics as a mass spectrometry-guided genome-mining method for microbial glycosylated molecules. Proc. Natl Acad. Sci. USA 110, E4407–E4416 (2013).
Mohimani, H. et al. Automated genome mining of ribosomal peptide natural products. ACS Chem. Biol. 9, 1545–1551 (2014).
Cao, L. et al. MetaMiner: a scalable peptidogenomics approach for discovery of ribosomal peptide natural products with blind modifications from microbial communities. Cell Syst. 9, 600–608 (2019).
Dejong, C. A. et al. Polyketide and nonribosomal peptide retro-biosynthesis and global gene cluster matching. Nat. Chem. Biol. 12, 1007–1014 (2016).
Goering, A. W. et al. Metabologenomics: correlation of microbial gene clusters with metabolites drives discovery of a nonribosomal peptide with an unusual amino acid monomer. ACS Cent. Sci. 2, 99–108 (2016).
Izumikawa, M. et al. Pyrrolidine-containing peptides, JBIR-126,-148, and-149, from Streptomyces sp. NBRC 111228. Tetrahedron Lett. 56, 5333–5336 (2015).
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).
Mohimani, H. et al. Dereplication of microbial metabolites through database search of mass spectra. Nat. Commun. 9, 4035 (2018).
Sieber, S., Grendelmeier, S. M., Harris, L. A., Mitchell, D. A. & Gademann, K. Microviridin 1777: a toxic chymotrypsin inhibitor discovered by a metabologenomic approach. J. Nat. Prod. 83, 438–446 (2020).
Wu, C. et al. Lugdunomycin, an angucycline-derived molecule with unprecedented chemical. Architecture. Angew. Chem. Int. Ed. 58, 2809–2814 (2019).
Quinn, R. A. et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129 (2020).
Ernst, M. et al. MolNetEnhancer: enhanced molecular networks by integrating metabolome mining and annotation tools. Metabolites 9, 144 (2019).
Schorn, M. A. et al. A community resource for paired genomic and metabolomic data mining. Nat. Chem. Biol. 17, 363–368 (2021).
Cimermancic, P. et al. Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell 158, 412–421 (2014).
Hannigan, G. D. et al. A deep learning genome-mining strategy for biosynthetic gene cluster prediction. Nucleic Acids Res. 47, e110 (2019).
Navarro-Munoz, J. C. et al. A computational framework to explore large-scale biosynthetic diversity. Nat. Chem. Biol. 16, 60–68 (2020).
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).
Kautsar, S. A., van der Hooft, J. J. J., de Ridder, D. & Medema, M. H. BiG-SLiCE: a highly scalable tool maps the diversity of 1.2 million biosynthetic gene clusters. Gigascience 10, 1–17 (2021).
Nothias, L. F. et al. Bioactivity-based molecular networking for the discovery of drug leads in natural product bioassay-guided fractionation. J. Nat. Prod. 81, 758–767 (2018).
Gerlt, J. A. et al. Enzyme Function Initiative-Enzyme Similarity Tool (EFI-EST): a web tool for generating protein sequence similarity networks. Biochim. Biophys. Acta 1854, 1019–1037 (2015).
Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498–2504 (2003).
Li, Y. X., Zhong, Z., Zhang, W. P. & Qian, P. Y. Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining. Nat. Commun. 9, 3273 (2018).
de Rond, T., Asay, J. E. & Moore, B. S. Co-occurrence of enzyme domains guides the discovery of an oxazolone synthetase. Nat. Chem. Biol. 17, 794–799 (2021).
Thaker, M. N., Waglechner, N. & Wright, G. D. Antibiotic resistance-mediated isolation of scaffold-specific natural product producers. Nat. Protoc. 9, 1469–1479 (2014).
Panter, F., Krug, D., Baumann, S. & Müller, R. Self-resistance guided genome mining uncovers new topoisomerase inhibitors from myxobacteria. Chem. Sci. 9, 4898–4908 (2018).
Mungan, M. D. et al. ARTS 2.0: feature updates and expansion of the Antibiotic Resistant Target Seeker for comparative genome mining. Nucleic Acids Res. 48, W546–W552 (2020).
Cruz-Morales, P. et al. Phylogenomic analysis of natural products biosynthetic gene clusters allows discovery of arseno-organic metabolites in model streptomycetes. Genome Biol. Evol. 8, 1906–1916 (2016).
Selem-Mojica, N., Aguilar, C., Gutierrez-Garcia, K., Martinez-Guerrero, C. E. & Barona-Gomez, F. EvoMining reveals the origin and fate of natural product biosynthetic enzymes. Micro. Genom. 5, e000260 (2019).
Prihoda, D. et al. The application potential of machine learning and genomics for understanding natural product diversity, chemistry, and therapeutic translatability. Nat. Product. Rep. 38, 1100–1108 (2021).
Baltz, R. H. Gifted microbes for genome mining and natural product discovery. J. Ind. Microbiol. Biotechnol. 44, 573–588 (2017).
Barka, E. A. et al. Taxonomy, physiology, and natural products of actinobacteria. Microbiol. Mol. Biol. Rev. 80, 1–43 (2016).
Watve, M. G., Tickoo, R., Jog, M. M. & Bhole, B. D. How many antibiotics are produced by the genus Streptomyces? Arch. Microbiol. 176, 386–390 (2001).
Baltz, R. H. Natural product drug discovery in the genomic era: realities, conjectures, misconceptions, and opportunities. J. Ind. Microbiol. Biotechnol. 46, 281–299 (2019).
Grubbs, K. J. et al. Large-scale bioinformatics analysis of bacillus genomes uncovers conserved roles of natural products in bacterial physiology. mSystems 2, e00040 (2017).
Leao, T. et al. Comparative genomics uncovers the prolific and distinctive metabolic potential of the cyanobacterial genus Moorea. Proc. Natl Acad. Sci. USA 114, 3198–3203 (2017).
Hillenmeyer, M. E., Vandova, G. A., Berlew, E. E. & Charkoudian, L. K. Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters. Proc. Natl Acad. Sci. USA 112, 13952–13957 (2015).
Pfeifer, B. A., Admiraal, S. J., Gramajo, H., Cane, D. E. & Khosla, C. Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science 291, 1790–1792 (2001).
Vieweg, L., Reichau, S., Schobert, R., Leadlay, P. F. & Sussmuth, R. D. Recent advances in the field of bioactive tetronates. Nat. Prod. Rep. 31, 1554–1584 (2014).
Leikoski, N. et al. Genome mining expands the chemical diversity of the cyanobactin family to include highly modified linear peptides. Chem. Biol. 20, 1033–1043 (2013).
Doroghazi, J. R. et al. A roadmap for natural product discovery based on large-scale genomics and metabolomics. Nat. Chem. Biol. 10, 963–968 (2014).
Hoffmann, T. et al. Correlating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria. Nat. Commun. 9, 803 (2018).
Antony-Babu, S. et al. Multiple Streptomyces species with distinct secondary metabolomes have identical 16S rRNA gene sequences. Sci. Rep. 7, 11089 (2017).
Adamek, M. et al. Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species. BMC Genomics 19, 426 (2018).
Ziemert, N. et al. Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proc. Natl Acad. Sci. USA 111, E1130–E1139 (2014).
Tobias, N. J. et al. Natural product diversity associated with the nematode symbionts Photorhabdus and Xenorhabdus. Nat. Microbiol. 2, 1676–1685 (2017).
Pye, C. R., Bertin, M. J., Lokey, R. S., Gerwick, W. H. & Linington, R. G. Retrospective analysis of natural products provides insights for future discovery trends. Proc. Natl Acad. Sci. USA 114, 5601–5606 (2017).
Goodrich-Blair, H. & Clarke, D. J. Mutualism and pathogenesis in Xenorhabdus and Photorhabdus: two roads to the same destination. Mol. Microbiol. 64, 260–268 (2007).
Reimer, D., Luxenburger, E., Brachmann, A. O. & Bode, H. B. A new type of pyrrolidine biosynthesis is involved in the late steps of xenocoumacin production in Xenorhabdus nematophila. Chembiochem 10, 1997–2001 (2009).
Eleftherianos, I. et al. An antibiotic produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition. Proc. Natl Acad. Sci. USA 104, 2419–2424 (2007).
Panthee, S., Hamamoto, H., Paudel, A. & Sekimizu, K. Lysobacter species: a potential source of novel antibiotics. Arch. Microbiol. 198, 839–845 (2016).
Nozaki, Y. et al. Cephabacins, new cephem antibiotics of bacterial origin. IV. Antibacterial activities, stability to β-lactamases and mode of action. J. Antibiot. 37, 1555–1565 (1984).
Lee, W. et al. The mechanism of action of lysobactin. J. Am. Chem. Soc. 138, 100–103 (2016).
Sang, M. et al. Identification of an anti-MRSA cyclic lipodepsipeptide, WBP-29479A1, by genome mining of Lysobacter antibioticus. Org. Lett. 21, 6432–6436 (2019).
Wu, Y. & Seyedsayamdost, M. R. The polyene natural product thailandamide A inhibits fatty acid biosynthesis in Gram-positive and Gram-negative bacteria. Biochemistry 57, 4247–4251 (2018).
Wang, C. et al. Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J. Nat. Prod. 74, 2031–2038 (2011).
Biggins, J. B., Gleber, C. D. & Brady, S. F. Acyldepsipeptide HDAC inhibitor production induced in Burkholderia thailandensis. Org. Lett. 13, 1536–1539 (2011).
Biggins, J. B., Liu, X., Feng, Z. & Brady, S. F. Metabolites from the induced expression of cryptic single operons found in the genome of Burkholderia pseudomallei. J. Am. Chem. Soc. 133, 1638–1641 (2011).
Franke, J., Ishida, K. & Hertweck, C. Genomics-driven discovery of burkholderic acid, a noncanonical, cryptic polyketide from human pathogenic Burkholderia species. Angew. Chem. Int. Ed. 51, 11611–11615 (2012).
Seyedsayamdost, M. R. et al. Quorum-sensing-regulated bactobolin production by Burkholderia thailandensis E264. Org. Lett. 12, 716–719 (2010).
Park, J. D. et al. Thailandenes, cryptic polyene natural products isolated from Burkholderia thailandensis using phenotype-guided transposon mutagenesis. ACS Chem. Biol. 15, 1195–1203 (2020).
Mullins, A. J. et al. Genome mining identifies cepacin as a plant-protective metabolite of the biopesticidal bacterium Burkholderia ambifaria. Nat. Microbiol. 4, 996–1005 (2019).
Xu, F. et al. A genetics-free method for high-throughput discovery of cryptic microbial metabolites. Nat. Chem. Biol. 15, 161–168 (2019).
Ma, M. et al. Complete genome sequence of Paenibacillus mucilaginosus 3016, a bacterium functional as microbial fertilizer. J. Bacteriol. 194, 2777–2778 (2012).
Baindara, P., Nayudu, N. & Korpole, S. Whole genome mining reveals a diverse repertoire of lanthionine synthetases and lanthipeptides among the genus Paenibacillus. J. Appl. Microbiol. 128, 473–490 (2020).
Velkov, T., Thompson, P. E., Nation, R. L. & Li, J. Structure–activity relationships of polymyxin antibiotics. J. Med. Chem. 53, 1898–1916 (2010).
Vater, J. et al. Genome mining of the lipopeptide biosynthesis of Paenibacillus polymyxa E681 in combination with mass spectrometry: discovery of the lipoheptapeptide paenilipoheptin. Chembiochem 19, 744–753 (2018).
Kiss, H. et al. Complete genome sequence of the filamentous gliding predatory bacterium Herpetosiphon aurantiacus type strain (114-95T). Stand. Genomic Sci. 5, 356–370 (2011).
Nett, M. et al. Siphonazole, an unusual metabolite from Herpetosiphon sp. Angew. Chem. Int. Ed. 45, 3863–3867 (2006).
Zhang, J., Polishchuk, E. A., Chen, J. & Ciufolini, M. A. Development of an oxazole conjunctive reagent and application to the total synthesis of siphonazoles. J. Org. Chem. 74, 9140–9151 (2009).
Schieferdecker, S. et al. Structure and absolute configuration of auriculamide, a natural product from the predatory bacterium Herpetosiphon aurantiacus. Eur. J. Org. Chem. 2015, 3057–3062 (2015).
Nakano, C., Oshima, M., Kurashima, N. & Hoshino, T. Identification of a new diterpene biosynthetic gene cluster that produces O-methylkolavelool in Herpetosiphon aurantiacus. Chembiochem 16, 772–781 (2015).
Chang, Y. J. et al. Non-contiguous finished genome sequence and contextual data of the filamentous soil bacterium Ktedonobacter racemifer type strain (SOSP1-21). Stand. Genom. Sci. 5, 97–111 (2011).
Ueoka, R. et al. Genome mining of oxidation modules in trans-acyltransferase polyketide synthases reveals a culturable source for lobatamides. Angew. Chem. Int. Ed. 59, 7761–7765 (2020).
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).
Rischer, M. et al. Biosynthesis, synthesis, and activities of barnesin A, a NRPS–PKS hybrid produced by an anaerobic Epsilonproteobacterium. ACS Chem. Biol. 13, 1990–1995 (2018).
Andrianasolo, E. H. et al. Ammonificins C and D, hydroxyethylamine chromene derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans. Mar. Drugs 10, 2300–2311 (2012).
Partida-Martinez, L. P. & Hertweck, C. Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature 437, 884–888 (2005).
Takeuchi, K. et al. Rhizoxin analogs contribute to the biocontrol activity of a newly isolated Pseudomonas strain. Mol. Plant. Microbe Interact. 28, 333–342 (2015).
Loper, J. E. et al. Rhizoxin analogs, orfamide A and chitinase production contribute to the toxicity of Pseudomonas protegens strain Pf-5 to Drosophila melanogaster. Environ. Microbiol. 18, 3509–3521 (2016).
Dudler, R. The role of bacterial phytotoxins in inhibiting the eukaryotic proteasome. Trends Microbiol. 22, 28–35 (2014).
Schellenberg, B., Bigler, L. & Dudler, R. Identification of genes involved in the biosynthesis of the cytotoxic compound glidobactin from a soil bacterium. Environ. Microbiol. 9, 1640–1650 (2007).
Stein, M. L. et al. One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor. Proc. Natl Acad. Sci. USA 109, 18367–18371 (2012).
Waspi, U., Blanc, D., Winkler, T., Ruedi, P. & Dudler, R. Syringolin, a novel peptide elicitor from Pseudomonas syringae pv. syringae that induces resistance to Pyricularia oryzae in rice. Mol. Plant. Microbe 11, 727–733 (1998).
Piel, J. et al. Exploring the chemistry of uncultivated bacterial symbionts: antitumor polyketides of the pederin family. J. Nat. Prod. 68, 472–479 (2005).
Piel, J. A polyketide synthase–peptide synthetase gene cluster from an uncultured bacterial symbiont of Paederus beetles. Proc. Natl Acad. Sci. USA 99, 14002–14007 (2002).
Nakabachi, A. et al. Defensive bacteriome symbiont with a drastically reduced genome. Curr. Biol. 23, 1478–1484 (2013).
Kampa, A. et al. Metagenomic natural product discovery in lichen provides evidence for a family of biosynthetic pathways in diverse symbioses. Proc. Natl Acad. Sci. USA 110, E3129–E3137 (2013).
Rust, M. et al. A multiproducer microbiome generates chemical diversity in the marine sponge Mycale hentscheli. Proc. Natl Acad. Sci. USA 117, 9508–9518 (2020).
Storey, M. A. et al. Metagenomic exploration of the marine sponge Mycale hentscheli uncovers multiple polyketide-producing bacterial symbionts. mBio 11, e02997 (2020).
Schleissner, C. et al. Bacterial production of a pederin analogue by a free-living marine Alphaproteobacterium. J. Nat. Prod. 80, 2170–2173 (2017).
Kust, A. et al. Discovery of a pederin family compound in a nonsymbiotic bloom-forming cyanobacterium. ACS Chem. Biol. 13, 1123–1129 (2018).
Chen, R., Wong, H. L. & Burns, B. P. New approaches to detect biosynthetic gene clusters in the environment. Medicines 6, 32 (2019).
Dittmann, E., Gugger, M., Sivonen, K. & Fewer, D. P. Natural product biosynthetic diversity and comparative genomics of the cyanobacteria. Trends Microbiol. 23, 642–652 (2015).
Long, R. A. & Azam, F. Antagonistic interactions among marine pelagic bacteria. Appl. Environ. Microbiol. 67, 4975–4983 (2001).
Villar, E. et al. The Ocean Gene Atlas: exploring the biogeography of plankton genes online. Nucleic Acids Res. 46, W289–W295 (2018).
Rateb, M. E. et al. Chaxamycins A–D, bioactive ansamycins from a hyper-arid desert Streptomyces sp. J. Nat. Prod. 74, 1491–1499 (2011).
Sunagawa, S. et al. Ocean plankton. Structure and function of the global ocean microbiome. Science 348, 1261359 (2015).
Kong, D. X., Jiang, Y. Y. & Zhang, H. Y. Marine natural products as sources of novel scaffolds: achievement and concern. Drug Discov. Today 15, 884–886 (2010).
Jensen, P. R., Moore, B. S. & Fenical, W. The marine actinomycete genus Salinispora: a model organism for secondary metabolite discovery. Nat. Prod. Rep. 32, 738–751 (2015).
Bister, B. et al. Abyssomicin C-A polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor of the p-aminobenzoic acid/tetrahydrofolate biosynthesis pathway. Angew. Chem. Int. Ed. 43, 2574–2576 (2004).
Felder, S. et al. Salimyxins and enhygrolides: antibiotic, sponge-related metabolites from the obligate marine myxobacterium Enhygromyxa salina. Chembiochem 14, 1363–1371 (2013).
Luesch, H., Yoshida, W. Y., Moore, R. E., Paul, V. J. & Corbett, T. H. Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula. J. Am. Chem. Soc. 123, 5418–5423 (2001).
Liu, Y., Law, B. K. & Luesch, H. Apratoxin a reversibly inhibits the secretory pathway by preventing cotranslational translocation. Mol. Pharmacol. 76, 91–104 (2009).
Hong, J. & Luesch, H. Largazole: from discovery to broad-spectrum therapy. Nat. Prod. Rep. 29, 449–456 (2012).
Walter, J. M. et al. Ecogenomics of the marine benthic filamentous Cyanobacterium adonisia. Microb. Ecol. 80, 249–265 (2020).
Offret, C. et al. Spotlight on antimicrobial metabolites from the marine bacteria Pseudoalteromonas: chemodiversity and ecological significance. Mar. Drugs 14, 129 (2016).
Silva, S. G., Blom, J., Keller-Costa, T. & Costa, R. Comparative genomics reveals complex natural product biosynthesis capacities and carbon metabolism across host-associated and free-living Aquimarina (Bacteroidetes, Flavobacteriaceae) species. Environ. Microbiol. 21, 4002–4019 (2019).
Sobolevskaya, M. P. et al. Controlling production of brominated cyclic depsipeptides by Pseudoalteromonas maricaloris KMM 636T. Lett. Appl. Microbiol. 40, 243–248 (2005).
Shiozawa, H. et al. Thiomarinol, a new hybrid antimicrobial antibiotic produced by a marine bacterium fermentation, isolation, structure, and antimicrobial activity. J. Antibiot. 46, 1834–1842 (1993).
Elshahawi, S. I. et al. Boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills. Proc. Natl Acad. Sci. USA 110, E295–E304 (2013).
Chevrette, M. G. et al. The antimicrobial potential of Streptomyces from insect microbiomes. Nat. Commun. 10, 516 (2019).
Kroiss, J. et al. Symbiotic Streptomycetes provide antibiotic combination prophylaxis for wasp offspring. Nat. Chem. Biol. 6, 261–263 (2010).
Nyholm, S. V. In the beginning: egg–microbe interactions and consequences for animal hosts. Phil. Trans. R. Soc. B 375, 20190593 (2020).
Kador, M., Horn, M. A. & Dettner, K. Novel oligonucleotide probes for in situ detection of pederin-producing endosymbionts of Paederus riparius rove beetles (Coleoptera: Staphylinidae). FEMS Microbiol. Lett. 319, 73–81 (2011).
Florez, L. V., Biedermann, P. H., Engl, T. & Kaltenpoth, M. Defensive symbioses of animals with prokaryotic and eukaryotic microorganisms. Nat. Prod. Rep. 32, 904–936 (2015).
Daniel-Ivad, M., Pimentel-Elardo, S. & Nodwell, J. R. Control of specialized metabolism by signaling and transcriptional regulation: opportunities for new platforms for drug discovery? Annu. Rev. Microbiol. 72, 25–48 (2018).
Shi, Y. et al. Synthetic multispecies microbial communities reveals shifts in secondary metabolism and facilitates cryptic natural product discovery. Environ. Microbiol. 19, 3606–3618 (2017).
Adnani, N. et al. Coculture of marine invertebrate-associated bacteria and interdisciplinary technologies enable biosynthesis and discovery of a new antibiotic, keyicin. ACS Chem. Biol. 12, 3093–3102 (2017).
Zipperer, A. et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535, 511–516 (2016).
Bitschar, K. et al. Lugdunin amplifies innate immune responses in the skin in synergy with host- and microbiota-derived factors. Nat. Commun. 10, 2730 (2019).
Korp, J., Vela Gurovic, M. S. & Nett, M. Antibiotics from predatory bacteria. Beilstein J. Org. Chem. 12, 594–607 (2016).
Xiao, Y., Wei, X., Ebright, R. & Wall, D. Antibiotic production by myxobacteria plays a role in predation. J. Bacteriol. 193, 4626–4633 (2011).
Schieferdecker, S. et al. Structure and biosynthetic assembly of gulmirecins, macrolide antibiotics from the predatory bacterium Pyxidicoccus fallax. Chemistry 20, 15933–15940 (2014).
Baumann, S. et al. Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity. Angew. Chem. Int. Ed. 53, 14605–14609 (2014).
Jansen, R., Irschik, H., Reichenbach, H. & Hofle, G. Antibiotics from gliding bacteria, LXXX. Chivosazoles A–F: novel antifungal and cytotoxic macrolides from Sorangium cellulosum (myxobacteria). Liebigs Ann. Recl. 1997, 1725–1732 (1997).
Rachid, S., Gerth, K., Kochems, I. & Müller, R. Deciphering regulatory mechanisms for secondary metabolite production in the myxobacterium Sorangium cellulosum So ce56. Mol. Microbiol. 63, 1783–1796 (2007).
Schiefer, A. et al. Corallopyronin A for short-course anti-wolbachial, macrofilaricidal treatment of filarial infections. PLoS Negl. Trop. Dis. 14, e0008930 (2020).
Arp, J. et al. Synergistic activity of cosecreted natural products from amoebae-associated bacteria. Proc. Natl Acad. Sci. USA 115, 3758–3763 (2018).
Oh, D. C., Scott, J. J., Currie, C. R. & Clardy, J. Mycangimycin, a polyene peroxide from a mutualist Streptomyces sp. Org. Lett. 11, 633–636 (2009).
Van Arnam, E. B., Ruzzini, A. C., Sit, C. S., Currie, C. R. & Clardy, J. A rebeccamycin analog provides plasmid-encoded niche defense. J. Am. Chem. Soc. 137, 14272–14274 (2015).
Beemelmanns, C. et al. Macrotermycins A–D, glycosylated macrolactams from a termite-associated Amycolatopsis sp. M39. Org. Lett. 19, 1000–1003 (2017).
Parks, D. H. et al. A standardized bacterial taxonomy based on genome phylogeny substantially revises the tree of life. Nat. Biotechnol. 36, 996–1004 (2018).
Zan, J. et al. A microbial factory for defensive kahalalides in a tripartite marine symbiosis. Science 364, eaaw6732 (2019).
Freeman, M. F. et al. Metagenome mining reveals polytheonamides as posttranslationally modified ribosomal peptides. Science 338, 387–390 (2012).
Wilson, M. C. et al. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 506, 58–62 (2014).
Crits-Christoph, A., Diamond, S., Butterfield, C. N., Thomas, B. C. & Banfield, J. F. Novel soil bacteria possess diverse genes for secondary metabolite biosynthesis. Nature 558, 440–444 (2018).
Rappe, M. S., Connon, S. A., Vergin, K. L. & Giovannoni, S. J. Cultivation of the ubiquitous SAR11 marine bacterioplankton clade. Nature 418, 630–633 (2002).
Janssen, P. H., Yates, P. S., Grinton, B. E., Taylor, P. M. & Sait, M. Improved culturability of soil bacteria and isolation in pure culture of novel members of the divisions Acidobacteria, Actinobacteria, Proteobacteria, and Verrucomicrobia. Appl. Environ. Microbiol. 68, 2391–2396 (2002).
Nguyen, T. M. et al. Effective soil extraction method for cultivating previously uncultured soil bacteria. Appl. Environ. Microbiol. 84, e01145 (2018).
Condren, A. R. et al. Addition of insoluble fiber to isolation media allows for increased metabolite diversity of lab-cultivable microbes derived from zebrafish gut samples. Gut Microbes 11, 1064–1076 (2020).
Lagier, J. C. et al. Culture of previously uncultured members of the human gut microbiota by culturomics. Nat. Microbiol. 1, 16203 (2016).
Tyson, G. W. et al. Genome-directed isolation of the key nitrogen fixer Leptospirillum ferrodiazotrophum sp. nov. from an acidophilic microbial community. Appl. Environ. Microbiol. 71, 6319–6324 (2005).
Cross, K. L. et al. Targeted isolation and cultivation of uncultivated bacteria by reverse genomics. Nat. Biotechnol. 37, 1314 (2019).
Nichols, D. et al. Use of ichip for high-throughput in situ cultivation of “uncultivable” microbial species. Appl. Environ. Microbiol. 76, 2445–2450 (2010).
Ling, L. L. et al. A new antibiotic kills pathogens without detectable resistance. Nature 517, 455 (2015).
Ueoka, R. et al. Metabolic and evolutionary origin of actin-binding polyketides from diverse organisms. Nat. Chem. Biol. 11, 705–712 (2015).
He, H. et al. Cyanobufalins: cardioactive toxins from cyanobacterial blooms. J. Nat. Prod. 81, 2576–2581 (2018).
Craig, J. W., Chang, F. Y., Kim, J. H., Obiajulu, S. C. & Brady, S. F. Expanding small-molecule functional metagenomics through parallel screening of broad-host-range cosmid environmental DNA libraries in diverse proteobacteria. Appl. Environ. Microbiol. 76, 1633–1641 (2010).
Long, P. F., Dunlap, W. C., Battershill, C. N. & Jaspars, M. Shotgun cloning and heterologous expression of the patellamide gene cluster as a strategy to achieving sustained metabolite production. Chembiochem 6, 1760–1765 (2005).
Theodorou, E., Scanga, R., Twardowski, M., Snyder, M. P. & Brouzes, E. A droplet microfluidics based platform for mining metagenomic libraries for natural compounds. Micromachines 8, 230 (2017).
Brady, S. F. Construction of soil environmental DNA cosmid libraries and screening for clones that produce biologically active small molecules. Nat. Protoc. 2, 1297–1305 (2007).
Huo, L. et al. Heterologous expression of bacterial natural product biosynthetic pathways. Nat. Prod. Rep. 36, 1412–1436 (2019).
Bitok, J. K., Lemetre, C., Ternei, M. A. & Brady, S. F. Identification of biosynthetic gene clusters from metagenomic libraries using PPTase complementation in a Streptomyces host. FEMS Microbiol. Lett. 364, fnx155 (2017).
Iqbal, H. A., Low-Beinart, L., Obiajulu, J. U. & Brady, S. F. Natural product discovery through improved functional metagenomics in Streptomyces. J. Am. Chem. Soc. 138, 9341–9344 (2016).
Chang, F. Y., Ternei, M. A., Calle, P. Y. & Brady, S. F. Targeted metagenomics: finding rare tryptophan dimer natural products in the environment. J. Am. Chem. Soc. 137, 6044–6052 (2015).
Charlop-Powers, Z. et al. Urban park soil microbiomes are a rich reservoir of natural product biosynthetic diversity. Proc. Natl Acad. Sci. USA 113, 14811–14816 (2016).
Kang, H. S. & Brady, S. F. Arixanthomycins A–C: phylogeny-guided discovery of biologically active eDNA-derived pentangular polyphenols. ACS Chem. Biol. 9, 1267–1272 (2014).
Kim, J. H. et al. Cloning large natural product gene clusters from the environment: piecing environmental DNA gene clusters back together with TAR. Biopolymers 93, 833–844 (2010).
Hrvatin, S. & Piel, J. Rapid isolation of rare clones from highly complex DNA libraries by PCR analysis of liquid gel pools. J. Microbiol. Methods 68, 434–436 (2007).
Libis, V. et al. Uncovering the biosynthetic potential of rare metagenomic DNA using co-occurrence network analysis of targeted sequences. Nat. Commun. 10, 3848 (2019).
Saeed, I., Tang, S. L. & Halgamuge, S. K. Unsupervised discovery of microbial population structure within metagenomes using nucleotide base composition. Nucleic Acids Res. 40, e34 (2012).
Donia, M. S. et al. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 158, 1402–1414 (2014).
Agarwal, V. et al. Metagenomic discovery of polybrominated diphenyl ether biosynthesis by marine sponges. Nat. Chem. Biol. 13, 537–543 (2017).
Kwan, J. C. et al. Genome streamlining and chemical defense in a coral reef symbiosis. Proc. Natl Acad. Sci. USA 109, 20655–20660 (2012).
Sudek, S. et al. Identification of the putative bryostatin polyketide synthase gene cluster from “Candidatus Endobugula sertula”, the uncultivated microbial symbiont of the marine bryozoan Bugula neritina. J. Nat. Prod. 70, 67–74 (2007).
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).
Tianero, M. D., Balaich, J. N. & Donia, M. S. Localized production of defence chemicals by intracellular symbionts of Haliclona sponges. Nat. Microbiol. 4, 1149–1159 (2019).
Schofield, M. M., Jain, S., Porat, D., Dick, G. J. & Sherman, D. H. Identification and analysis of the bacterial endosymbiont specialized for production of the chemotherapeutic natural product ET-743. Environ. Microbiol. 17, 3964–3975 (2015).
Sun, M. K. & Alkon, D. L. Bryostatin-1: pharmacology and therapeutic potential as a CNS drug. CNS Drug Rev. 12, 1–8 (2006).
Miguel-Lillo, B., Valenzuela, B., Peris-Ribera, J. E., Soto-Matos, A. & Perez-Ruixo, J. J. Population pharmacokinetics of kahalalide F in advanced cancer patients. Cancer Chemother. Pharmacol. 76, 365–374 (2015).
Gaitanos, T. N. et al. Peloruside A does not bind to the taxoid site on β-tubulin and retains its activity in multidrug-resistant cell lines. Cancer Res. 64, 5063–5067 (2004).
Schmidt, E. W. et al. Patellamide A and C biosynthesis by a microcin-like pathway in Prochloron didemni, the cyanobacterial symbiont of Lissoclinum patella. Proc. Natl Acad. Sci. USA 102, 7315–7320 (2005).
Smith, T. E. et al. Accessing chemical diversity from the uncultivated symbionts of small marine animals. Nat. Chem. Biol. 14, 179–185 (2018).
Piel, J. & Cahn, J. Opening up the single-cell toolbox for microbial natural products research. Angew. Chem. Int. Ed. Engl. 60, 18412–18428 (2019).
Grindberg, R. V. et al. Single cell genome amplification accelerates identification of the apratoxin biosynthetic pathway from a complex microbial assemblage. PLoS ONE 6, e18565 (2011).
Miyaoka, R. et al. In situ detection of antibiotic amphotericin B produced in Streptomyces nodosus using Raman microspectroscopy. Mar. Drugs 12, 2827–2839 (2014).
Lee, K. S. et al. An automated Raman-based platform for the sorting of live cells by functional properties. Nat. Microbiol. 4, 1035–1048 (2019).
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).
Elfeki, M., Alanjary, M., Green, S. J., Ziemert, N. & Murphy, B. T. Assessing the efficiency of cultivation techniques to recover natural product biosynthetic gene populations from sediment. ACS Chem. Biol. 13, 2074–2081 (2018).
Ju, K. S. et al. Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes. Proc. Natl Acad. Sci. USA 112, 12175–12180 (2015).
Letzel, A. C. et al. Genomic insights into specialized metabolism in the marine actinomycete Salinispora. Environ. Microbiol. 19, 3660–3673 (2017).
Gilbert, J. A., Jansson, J. K. & Knight, R. The Earth Microbiome Project: successes and aspirations. BMC Biol. 12, 69 (2014).
Eckert, E. M. et al. Every fifth published metagenome is not available to science. PLoS Biol. 18, e3000698 (2020).
Chassagne, F., Cabanac, G., Hubert, G., David, B. & Marti, G. The landscape of natural product diversity and their pharmacological relevance from a focus on the Dictionary of Natural Products®. Phytochem. Rev. 18, 601–622 (2019).
Walker, A. S. & Clardy, J. A machine learning bioinformatics method to predict biological activity from biosynthetic gene clusters. J. Chem. Inf. Model. 61, 2560–2571 (2021).
Mast, Y. et al. Characterization of the ‘pristinamycin supercluster’ of Streptomyces pristinaespiralis. Microb. Biotechnol. 4, 192–206 (2011).
Mrak, P. et al. Discovery of the actinoplanic acid pathway in Streptomyces rapamycinicus reveals a genetically conserved synergism with rapamycin. J. Biol. Chem. 293, 19982–19995 (2018).
McCauley, E. P. et al. Highlights of marine natural products having parallel scaffolds found from marine-derived bacteria, sponges, and tunicates. J. Antibiot. 73, 504–525 (2020).
Wakimoto, T. et al. Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont. Nat. Chem. Biol. 10, 648–655 (2014).
J.P. acknowledges funding by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 742739), the Gordon and Betty Moore Foundation (#9204, https://doi.org/10.37807/GBMF9204), the Swiss National Science Foundation (205320_185077 and NRP 72 ‘Antimicrobial resistance’, 407240_167051), the Helmut Horten Foundation and the Promedica Foundation.
The authors declare no competing interests.
Peer review information
Nature Reviews Drug Discovery thanks Ronald Quinn and other anonymous reviewers for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The Natural Product Magnetic Resonance Database Project: http://www.np-mrd.org
The process of recognizing already known biosynthetic gene clusters (BGCs) or compounds and eliminating them from downstream analysis.
- Biosynthetic gene clusters
(BGCs). Gene loci encoding proteins involved in natural product (NP) biosynthesis, resistance and regulation.
Structurally related compounds with overall high similarity.
Methods that explore mixed communities at the DNA level.
Enzymes modifying ribosomally synthesized and post-translationally modified peptide (RiPP) precursors or proteins.
Compounds able to complex iron with high affinity.
Members of a beneficial symbiosis.
- Microbial dark matter
The large and as yet poorly explored portion of microbial diversity that has eluded laboratory cultivation.
Sets of overlapping DNA sequencing reads from the same genomic source.
The computational grouping of contigs with shared DNA properties, such as sequence coverage or oligonucleotide frequency, after metagenome sequencing.
About this article
Cite this article
Hemmerling, F., Piel, J. Strategies to access biosynthetic novelty in bacterial genomes for drug discovery. Nat Rev Drug Discov 21, 359–378 (2022). https://doi.org/10.1038/s41573-022-00414-6
This article is cited by
Insights into the Biological Properties of Ligands and Identity of Operator Site for LanK Protein Involved in Landomycin Production
Current Microbiology (2024)
Nature Communications (2023)
Journal of Natural Medicines (2023)
The little things that matter: how bioprospecting microbial biodiversity can build towards the realization of United Nations Sustainable Development Goals
npj Biodiversity (2022)