Ecology and genomics of Actinobacteria: new concepts for natural product discovery

Abstract

Actinobacteria constitute a highly diverse bacterial phylum with an unrivalled metabolic versatility. They produce most of the clinically used antibiotics and a plethora of other natural products with medical or agricultural applications. Modern ‘omics’-based technologies have revealed that the genomic potential of Actinobacteria greatly outmatches the known chemical space. In this Review, we argue that combining insights into actinobacterial ecology with state-of-the-art computational approaches holds great promise to unlock this unexplored reservoir of actinobacterial metabolism. This enables the identification of small molecules and other stimuli that elicit the induction of poorly expressed biosynthetic gene clusters, which should help reinvigorate screening efforts for their precious bioactive natural products.

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Fig. 1: From biological understanding to elicitation of BGCs.
Fig. 2: BGC distribution and evolution in Streptomyces chromosomes.
Fig. 3: Natural products of Actinobacteria in host–microorganism and microorganism–microorganism interactions.
Fig. 4: Omics strategies for BGC prioritization and elicitation.

References

  1. 1.

    Whitman, W. B. et al. Bergey’s Manual of Systematic Bacteriology: Volume 5: The Actinobacteria (Springer Science & Business Media, 2012).

  2. 2.

    van der Meij, A., Worsley, S. F., Hutchings, M. I. & van Wezel, G. P. Chemical ecology of antibiotic production by actinomycetes. FEMS Microbiol. Rev. 41, 392–416 (2017).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Barka, E. A. et al. Taxonomy, physiology, and natural products of Actinobacteria. Microbiol. Mol. Biol. Rev. 80, 1–43 (2016).

    PubMed  Google Scholar 

  4. 4.

    Bérdy, J. Bioactive microbial metabolites. J. Antibiot. 58, 1–26 (2005).

    PubMed  Google Scholar 

  5. 5.

    Hopwood, D. A. Streptomyces in Nature and Medicine: the Antibiotic Makers (Oxford Univ. Press, 2007).

  6. 6.

    Vrancken, K. & Anne, J. Secretory production of recombinant proteins by Streptomyces. Future Microbiol. 4, 181–188 (2009).

    CAS  PubMed  Google Scholar 

  7. 7.

    Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).

    CAS  PubMed  Google Scholar 

  8. 8.

    Davies, J. & Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 74, 417–433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Cooper, M. A. & Shlaes, D. Fix the antibiotics pipeline. Nature 472, 32 (2011).

    CAS  PubMed  Google Scholar 

  10. 10.

    Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug. Discov. 6, 29–40 (2007).

    CAS  PubMed  Google Scholar 

  11. 11.

    Baltz, R. H. Antimicrobials from actinomycetes: back to the future. Microbe 2, 125–131 (2007).

    Google Scholar 

  12. 12.

    Baltz, R. H. Renaissance in antibacterial discovery from actinomycetes. Curr. Opin. Pharmacol. 8, 557–563 (2008).

    CAS  PubMed  Google Scholar 

  13. 13.

    Bentley, S. D. et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417, 141–147 (2002).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Ikeda, H. et al. Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat. Biotechnol. 21, 526–531 (2003).

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    van den Berg, M. A. et al. Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum. Nat. Biotechnol. 26, 1161–1168 (2008).

    CAS  PubMed  Google Scholar 

  16. 16.

    Bode, H. B., Bethe, B., Hofs, R. & Zeeck, A. Big effects from small changes: possible ways to explore nature’s chemical diversity. Chembiochem 3, 619–627 (2002).

    CAS  PubMed  Google Scholar 

  17. 17.

    Romano, S., Jackson, S. A., Patry, S. & Dobson, A. D. W. Extending the “One strain many compounds” (OSMAC) principle to marine microorganisms. Mar. Drugs 16, 244 (2018).

    PubMed Central  Google Scholar 

  18. 18.

    Wu, C. et al. Lugdunomycin, an angucycline-derived molecule with unprecedented chemical architecture. Angew. Chem. Int. Ed. Engl. 58, 2809–2814 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Wright, E. S. & Vetsigian, K. H. Inhibitory interactions promote frequent bistability among competing bacteria. Nat. Commun. 7, 11274 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Hibbing, M. E., Fuqua, C., Parsek, M. R. & Peterson, S. B. Bacterial competition: surviving and thriving in the microbial jungle. Nat. Rev. Microbiol. 8, 15–25 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Abrudan, M. I. et al. Socially mediated induction and suppression of antibiosis during bacterial coexistence. Proc. Natl Acad. Sci. USA 112, 11054–11059 (2015).

    CAS  PubMed  Google Scholar 

  22. 22.

    Traxler, M. F. & Kolter, R. Natural products in soil microbe interactions and evolution. Nat. Prod. Rep. 32, 956–970 (2015).

    CAS  PubMed  Google Scholar 

  23. 23.

    Traxler, M. F., Watrous, J. D., Alexandrov, T., Dorrestein, P. C. & Kolter, R. Interspecies interactions stimulate diversification of the Streptomyces coelicolor secreted metabolome. mBio 4, e00459-13 (2013). This study uses nanospray desorption electrospray ionization mass spectrometry and MALDI–TOF imaging mass spectrometry to identify the chemical interactions that take place between actinomycete bacteria, revealing substantial changes in specialized metabolite production.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    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  Google Scholar 

  25. 25.

    Zhu, H., Sandiford, S. K. & van Wezel, G. P. Triggers and cues that activate antibiotic production by actinomycetes. J. Ind. Microbiol. Biotechnol. 41, 371–386 (2014).

    CAS  PubMed  Google Scholar 

  26. 26.

    Guerinot, M. L. Microbial iron transport. Annu. Rev. Microbiol. 48, 743–772 (1994).

    CAS  PubMed  Google Scholar 

  27. 27.

    Li, C., Ji, C. & Tang, B. Purification, characterisation and biological activity of melanin from Streptomyces sp. FEMS Microbiol. Lett. 365, fny077 (2018).

    CAS  Google Scholar 

  28. 28.

    Sadeghi, A. et al. Diversity of the ectoines biosynthesis genes in the salt tolerant Streptomyces and evidence for inductive effect of ectoines on their accumulation. Microbiol. Res. 169, 699–708 (2014).

    CAS  PubMed  Google Scholar 

  29. 29.

    Kroiss, J. et al. Symbiotic streptomycetes provide antibiotic combination prophylaxis for wasp offspring. Nat. Chem. Biol. 6, 261–263 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Raaijmakers, J. M. & Mazzola, M. Diversity and natural functions of antibiotics produced by beneficial and plant pathogenic bacteria. Annu. Rev. Phytopathol. 50, 403–424 (2012).

    CAS  PubMed  Google Scholar 

  31. 31.

    Doroghazi, J. R. & Metcalf, W. W. Comparative genomics of actinomycetes with a focus on natural product biosynthetic genes. BMC Genomics 14, 611 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Cimermancic, P. et al. Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell 158, 412–421 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Sriswasdi, S., Yang, C. C. & Iwasaki, W. Generalist species drive microbial dispersion and evolution. Nat. Commun. 8, 1162 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Shimkets, L. J. in Bacterial Genomes: Physical Structure and Analysis (eds de Bruijn, F. J., Lupski, J. R. & Weinstock, G. M.) 5–11 (Chapman & Hall, 1998).

  35. 35.

    Fraser, C. M. et al. The minimal gene complement of Mycoplasma genitalium. Science 270, 397–403 (1995).

    CAS  PubMed  Google Scholar 

  36. 36.

    Salem, H. et al. Drastic genome reduction in an herbivore’s pectinolytic symbiont. Cell 171, 1520–1531 (2017).

    CAS  PubMed  Google Scholar 

  37. 37.

    Davies, J. Millennium bugs. Trends Cell Biol. 9, M2–M5 (1999).

    CAS  PubMed  Google Scholar 

  38. 38.

    Claessen, D., Rozen, D. E., Kuipers, O. P., Sogaard-Andersen, L. & van Wezel, G. P. Bacterial solutions to multicellularity: a tale of biofilms, filaments and fruiting bodies. Nat. Rev. Microbiol. 12, 115–124 (2014).

    CAS  PubMed  Google Scholar 

  39. 39.

    Flärdh, K. & Buttner, M. J. Streptomyces morphogenetics: dissecting differentiation in a filamentous bacterium. Nat. Rev. Microbiol. 7, 36–49 (2009).

    PubMed  Google Scholar 

  40. 40.

    Chater, K. F. & Losick, R. in Bacteria as Multicellular Organisms (eds Shapiro, J. A. & Dworkin, M.) 149–182 (Oxford University Press, 1997).

  41. 41.

    Merrick, M. J. A morphological and genetic mapping study of bald colony mutants of Streptomyces coelicolor. J. Gen. Microbiol. 96, 299–315 (1976).

    CAS  PubMed  Google Scholar 

  42. 42.

    Hopwood, D. A., Wildermuth, H. & Palmer, H. M. Mutants of Streptomyces coelicolor defective in sporulation. J. Gen. Microbiol. 61, 397–408 (1970).

    CAS  PubMed  Google Scholar 

  43. 43.

    Bibb, M. J. Regulation of secondary metabolism in streptomycetes. Curr. Opin. Microbiol. 8, 208–215 (2005).

    CAS  PubMed  Google Scholar 

  44. 44.

    van der Heul, H. U., Bilyk, B. L., McDowall, K. J., Seipke, R. F. & van Wezel, G. P. Regulation of antibiotic production in Actinobacteria: new perspectives from the post-genomic era. Nat. Prod. Rep. 35, 575–604 (2018).

    PubMed  Google Scholar 

  45. 45.

    Manteca, A. A death round affecting a young compartmentalized mycelium precedes aerial mycelium dismantling in confluent surface cultures of Streptomyces antibioticus. Microbiology 151, 3689–3697 (2005).

    CAS  PubMed  Google Scholar 

  46. 46.

    Manteca, A., Mader, U., Connolly, B. A. & Sanchez, J. A proteomic analysis of Streptomyces coelicolor programmed cell death. Proteomics 6, 6008–6022 (2006).

    CAS  PubMed  Google Scholar 

  47. 47.

    Tenconi, E., Traxler, M. F., Hoebreck, C., van Wezel, G. P. & Rigali, S. Production of prodiginines is part of a programmed cell death process in Streptomyces coelicolor. Front. Microbiol. 9, 1742 (2018).

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Ohnishi, Y. et al. Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J. Bacteriol. 190, 4050–4060 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Gomez-Escribano, J. P. et al. Structure and biosynthesis of the unusual polyketide alkaloid coelimycin P1, a metabolic product of the cpk gene cluster of Streptomyces coelicolor M145. Chem. Sci. 3, 2716–2720 (2012).

    CAS  Google Scholar 

  50. 50.

    Wu, C. et al. Expanding the chemical space for natural products by Aspergillus-Streptomyces co-cultivation and biotransformation. Sci. Rep. 5, 10868 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Challis, G. L. & Hopwood, D. A. Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc. Natl Acad. Sci. USA 100, 14555–14561 (2003).

    CAS  PubMed  Google Scholar 

  52. 52.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

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

    CAS  PubMed  Google Scholar 

  54. 54.

    Seipke, R. F., Kaltenpoth, M. & Hutchings, M. I. Streptomyces as symbionts: an emerging and widespread theme? FEMS. Microbiol. Rev. 36, 862–876 (2012).

    CAS  Google Scholar 

  55. 55.

    Jensen, P. R., Williams, P. G., Oh, D.-C., Zeigler, L. & Fenical, W. Species-specific secondary metabolite production in marine actinomycetes of the genus Salinispora. Appl. Env. Microbiol. 73, 1146–1152 (2007).

    CAS  Google Scholar 

  56. 56.

    Yang, A. et al. Nitrosporeusines A and B, unprecedented thioester-bearing alkaloids from the Arctic Streptomyces nitrosporeus. Org. Lett. 15, 5366–5369 (2013).

    CAS  PubMed  Google Scholar 

  57. 57.

    Sayed, A. M. et al. Extreme environments: microbiology leading to specialized metabolites. J. Appl. Microbiol. 128, 630–657 (2019).

    PubMed  Google Scholar 

  58. 58.

    Chevrette, M. G. et al. The antimicrobial potential of Streptomyces from insect microbiomes. Nat. Commun. 10, 516 (2019). This article describes the biosynthetic potential of insect-associated streptomycetes and the use of metabolomics for strain prioritization, resulting in the discovery of a novel antifungal agent active against multidrug-resistant fungal strains.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    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). This work shows high pathway diversity in recently diverged Salinispora spp., providing evidence for evolutionary drivers that allow bacteria to maximize their capacity to produce diverse secondary metabolites.

    CAS  PubMed  Google Scholar 

  61. 61.

    Adamek, M. et al. Comparative genomics reveals phylogenetic distribution patterns of secondary metabolites in Amycolatopsis species. BMC Genomics 19, 426 (2018).

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Andam, C. P., Choudoir, M. J., Vinh Nguyen, A., Sol Park, H. & Buckley, D. H. Contributions of ancestral inter-species recombination to the genetic diversity of extant Streptomyces lineages. ISME J. 10, 1731–1741 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Tidjani, A. et al. Massive gene flux drives genome diversity between sympatric Streptomyces conspecifics. mBio 10, e01533-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    McDonald, B. R. & Currie, C. R. Lateral gene transfer dynamics in the ancient bacterial genus Streptomyces. mBio 8, e00644-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Medema, M. H., Cimermancic, P., Sali, A., Takano, E. & Fischbach, M. A. A systematic computational analysis of biosynthetic gene cluster evolution: lessons for engineering biosynthesis. PLoS Comp. Biol. 10, e1004016 (2014).

    Google Scholar 

  66. 66.

    Joynt, R. & Seipke, R. F. A phylogenetic and evolutionary analysis of antimycin biosynthesis. Microbiology 164, 28–39 (2018).

    CAS  PubMed  Google Scholar 

  67. 67.

    Chevrette, M. G. et al. Taxonomic and metabolic incongruence in the ancient genus Streptomyces. Front. Microbiol. 10, 2170 (2019).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Navarro-Munoz, J. C. et al. A computational framework to explore large-scale biosynthetic diversity. Nat. Chem. Biol. 16, 60–68 (2020). This work describes two computational tools, BiG-SCAPE and CORASON, designed to analyse BGC diversity in large genomic data sets.

    CAS  PubMed  Google Scholar 

  69. 69.

    Bruns, H. et al. Function-related replacement of bacterial siderophore pathways. ISME J. 12, 320–329 (2018). This study follows the evolutionary history of two siderophore biosynthesis pathways and reveals that acquisition of one pathway through HGT correlates to the loss of the other pathway.

    CAS  PubMed  Google Scholar 

  70. 70.

    Jensen, P. R. Natural products and the gene cluster revolution. Trends Microbiol. 24, 968–977 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Chater, K. F. & Chandra, G. The evolution of development in Streptomyces analysed by genome comparisons. FEMS Microbiol. Rev. 30, 651–672 (2006).

    CAS  PubMed  Google Scholar 

  72. 72.

    Ventura, M. et al. Genomics of Actinobacteria: tracing the evolutionary history of an ancient phylum. Microbiol. Mol. Biol. Rev. 71, 495–548 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Choulet, F. et al. Evolution of the terminal regions of the Streptomyces linear chromosome. Mol. Biol. Evol. 23, 2361–2369 (2006).

    CAS  PubMed  Google Scholar 

  74. 74.

    Bilyk, B., Horbal, L. & Luzhetskyy, A. Chromosomal position effect influences the heterologous expression of genes and biosynthetic gene clusters in Streptomyces albus J1074. Microb. Cell Fact. 16, 5 (2017).

    PubMed  PubMed Central  Google Scholar 

  75. 75.

    Letzel, A.-C. et al. Genomic insights into specialized metabolism in the marine actinomycete Salinispora. Env. Microbiol. 19, 3660–3673 (2017).

    CAS  Google Scholar 

  76. 76.

    Ghinet, M. G. et al. Uncovering the prevalence and diversity of integrating conjugative elements in Actinobacteria. PLoS One 6, e27846 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Kinashi, H., Shimaji, M. & Sakai, A. Giant linear plasmids in Streptomyces which code for antibiotic biosynthesis genes. Nature 328, 454–456 (1987).

    CAS  PubMed  Google Scholar 

  78. 78.

    Medema, M. H. et al. The sequence of a 1.8-Mb bacterial linear plasmid reveals a rich evolutionary reservoir of secondary metabolic pathways. Genome Biol. Evol. 2, 212–224 (2010).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Mochizuki, S. et al. The large linear plasmid pSLA2-L of Streptomyces rochei has an unusually condensed gene organization for secondary metabolism. Mol. Microbiol. 48, 1501–1510 (2003).

    CAS  PubMed  Google Scholar 

  80. 80.

    Hoskisson, P. A. & Fernández-Martínez, L. T. Regulation of specialised metabolites in Actinobacteria — expanding the paradigms. Env. Microbiol. Rep. 10, 231–238 (2018).

    Google Scholar 

  81. 81.

    Huang, J. et al. Cross-regulation among disparate antibiotic biosynthetic pathways of Streptomyces coelicolor. Mol. Microbiol. 58, 1276–1287 (2005).

    CAS  PubMed  Google Scholar 

  82. 82.

    McLean, T. C., Hoskisson, P. A. & Seipke, R. F. Coordinate regulation of antimycin and candicidin biosynthesis. mSphere 1, e00305-16 (2016).

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Martinet, L. et al. A single biosynthetic gene cluster is responsible for the production of bagremycin antibiotics and ferroverdin iron chelators. mBio 10, e01230-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Liu, G., Chater, K. F., Chandra, G., Niu, G. & Tan, H. Molecular regulation of antibiotic biosynthesis in Streptomyces. Microbiol. Mol. Biol. Rev. 77, 112–143 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Wietzorrek, A. & Bibb, M. A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold. Mol. Microbiol. 25, 1181–1184 (1997).

    CAS  PubMed  Google Scholar 

  86. 86.

    Autret, S., Nair, R. & Errington, J. Genetic analysis of the chromosome segregation protein Spo0J of Bacillus subtilis: evidence for separate domains involved in DNA binding and interactions with Soj protein. Mol. Microbiol. 41, 743–755 (2001).

    CAS  PubMed  Google Scholar 

  87. 87.

    Gramajo, H. C., Takano, E. & Bibb, M. J. Stationary-phase production of the antibiotic actinorhodin in Streptomyces coelicolor A3(2) is transcriptionally regulated. Mol. Microbiol. 7, 837–845 (1993).

    CAS  PubMed  Google Scholar 

  88. 88.

    Tomono, A., Tsai, Y., Yamazaki, H., Ohnishi, Y. & Horinouchi, S. Transcriptional control by A-factor of strR, the pathway-specific transcriptional activator for streptomycin biosynthesis in Streptomyces griseus. J. Bacteriol. 187, 5595–5604 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Lawlor, E. J., Baylis, H. A. & Chater, K. F. Pleiotropic morphological and antibiotic deficiencies result from mutations in a gene encoding a tRNA-like product in Streptomyces coelicolor A3(2). Genes Dev. 1, 1305–1310 (1987).

    CAS  PubMed  Google Scholar 

  90. 90.

    Fernandez-Moreno, M. A., Caballero, J. L., Hopwood, D. A. & Malpartida, F. The act cluster contains regulatory and antibiotic export genes, direct targets for translational control by the bldA tRNA gene of Streptomyces. Cell 66, 769–780 (1991).

    CAS  PubMed  Google Scholar 

  91. 91.

    Takano, E. γ-Butyrolactones: Streptomyces signalling molecules regulating antibiotic production and differentiation. Curr. Opin. Microbiol. 9, 287–294 (2006).

    CAS  PubMed  Google Scholar 

  92. 92.

    Willey, J. M. & Gaskell, A. A. Morphogenetic signaling molecules of the streptomycetes. Chem. Rev. 111, 174–187 (2011).

    CAS  PubMed  Google Scholar 

  93. 93.

    Tahlan, K. et al. Initiation of actinorhodin export in Streptomyces coelicolor. Mol. Microbiol. 63, 951–961 (2007).

    CAS  PubMed  Google Scholar 

  94. 94.

    Wang, L. et al. Autoregulation of antibiotic biosynthesis by binding of the end product to an atypical response regulator. Proc. Natl Acad. Sci. USA 106, 8617–8622 (2009).

    CAS  PubMed  Google Scholar 

  95. 95.

    Willems, A. R. et al. Crystal structures of the Streptomyces coelicolor TetR-like protein ActR alone and in complex with actinorhodin or the actinorhodin biosynthetic precursor (S)-DNPA. J. Mol. Biol. 376, 1377–1387 (2008).

    CAS  PubMed  Google Scholar 

  96. 96.

    Francis, I. M., Jourdan, S., Fanara, S., Loria, R. & Rigali, S. The cellobiose sensor CebR is the gatekeeper of Streptomyces scabies pathogenicity. mBio 6, e02018 (2015).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Rigali, S. et al. Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by. Streptomyces. EMBO Rep. 9, 670–675 (2008). This work is the first to describe a complete signalling pathway from an extracellular nutrient (GlcNAc) to the control of antibiotic biosynthetic pathways.

    CAS  PubMed  Google Scholar 

  98. 98.

    Nazari, B. et al. Chitin-induced gene expression involved in secondary metabolic pathways in Streptomyces coelicolor A3(2) grown in soil. Appl. Env. Microbiol. 79, 707–713 (2012).

    Google Scholar 

  99. 99.

    Craig, M. et al. Unsuspected control of siderophore production by N-acetylglucosamine in streptomycetes. Env. Microbiol. Rep. 4, 512–521 (2012).

    CAS  Google Scholar 

  100. 100.

    Świątek-Połatyńska, M. A. et al. Genome-wide analysis of in vivo binding of the master regulator DasR in Streptomyces coelicolor identifies novel non-canonical targets. PLoS One 10, e0122479 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Urem, M., Swiatek-Polatynska, M. A., Rigali, S. & van Wezel, G. P. Intertwining nutrient-sensory networks and the control of antibiotic production in Streptomyces. Mol. Microbiol. 102, 183–195 (2016).

    CAS  PubMed  Google Scholar 

  102. 102.

    Bode, H. Br., Bethe, B., Höfs, R. & Zeeck, A. Big effects from small changes: possible ways to explore nature’s chemical diversity. ChemBioChem 3, 619–627 (2002).

    CAS  PubMed  Google Scholar 

  103. 103.

    Zhu, H. et al. Eliciting antibiotics active against the ESKAPE pathogens in a collection of actinomycetes isolated from mountain soils. Microbiology 160, 1714–1725 (2014).

    CAS  PubMed  Google Scholar 

  104. 104.

    Hosaka, T. et al. Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12. Nat. Biotechnol. 27, 462–464 (2009).

    CAS  PubMed  Google Scholar 

  105. 105.

    Tanaka, Y. et al. Antibiotic overproduction by rpsL and rsmG mutants of various actinomycetes. Appl. Env. Microbiol. 75, 4919–4922 (2009).

    CAS  Google Scholar 

  106. 106.

    Bertrand, S. et al. Metabolite induction via microorganism co-culture: a potential way to enhance chemical diversity for drug discovery. Biotechnol. Adv. 32, 1180–1204 (2014).

    CAS  PubMed  Google Scholar 

  107. 107.

    Hoshino, S., Wakimoto, T., Onaka, H. & Abe, I. Chojalactones A–C, cytotoxic butanolides isolated from Streptomyces sp. cultivated with mycolic acid containing bacterium. Org. Lett. 17, 1501–1504 (2015).

    CAS  PubMed  Google Scholar 

  108. 108.

    Sugiyama, R. et al. 5-Alkyl-1,2,3,4-tetrahydroquinolines, new membrane-interacting lipophilic metabolites produced by combined culture of Streptomyces nigrescens and Tsukamurella pulmonis. Org. Lett. 17, 1918–1921 (2015).

    CAS  PubMed  Google Scholar 

  109. 109.

    Hsiao, N. H., Gottelt, M. & Takano, E. Chapter 6. Regulation of antibiotic production by bacterial hormones. Methods Enzymol. 458, 143–157 (2009).

    CAS  PubMed  Google Scholar 

  110. 110.

    Albright, J. C. et al. Large-scale metabolomics reveals a complex response of Aspergillus nidulans to epigenetic perturbation. ACS Chem. Biol., 1535-1541 (2015).

  111. 111.

    Craney, A., Ozimok, C., Pimentel-Elardo, S. M., Capretta, A. & Nodwell, J. R. Chemical perturbation of secondary metabolism demonstrates important links to primary metabolism. Chem. Biol. 19, 1020–1027 (2012). This work describes how screening a compound library for elicitors identified a novel family of molecules that activate antibiotic production.

    CAS  PubMed  Google Scholar 

  112. 112.

    Moon, K., Xu, F. & Seyedsayamdost, M. R. Cebulantin, a cryptic lanthipeptide antibiotic uncovered using bioactivity-coupled HiTES. Angew. Chem. Int. Ed. Engl. 58, 5973–5977 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Moon, K., Xu, F., Zhang, C. & Seyedsayamdost, M. R. Bioactivity-HiTES unveils cryptic antibiotics encoded in actinomycete bacteria. ACS Chem. Biol. 14, 767–774 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Kramer, J., Ozkaya, O. & Kummerli, R. Bacterial siderophores in community and host interactions. Nat. Rev. Microbiol. 18, 152–163 (2020).

    CAS  PubMed  Google Scholar 

  115. 115.

    Niu, G., Chater, K. F., Tian, Y., Zhang, J. & Tan, H. Specialised metabolites regulating antibiotic biosynthesis in Streptomyces spp. FEMS Microbiol. Rev. 40, 554–573 (2016).

    CAS  PubMed  Google Scholar 

  116. 116.

    Onaka, H., Mori, Y., Igarashi, Y. & Furumai, T. Mycolic acid-containing bacteria induce natural-product biosynthesis in Streptomyces species. Appl. Env. Microbiol. 77, 400–406 (2011).

    CAS  Google Scholar 

  117. 117.

    Schroeckh, V. et al. Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc. Natl Acad. Sci. USA 106, 14558–14563 (2009).

    CAS  PubMed  Google Scholar 

  118. 118.

    Sung, A. A., Gromek, S. M. & Balunas, M. J. Upregulation and identification of antibiotic activity of a marine-derived Streptomyces sp. via co-cultures with human pathogens. Mar. Drugs 15 (2017).

  119. 119.

    Pérez, J. et al. Myxococcus xanthus induces actinorhodin overproduction and aerial mycelium formation by Streptomyces coelicolor. Microb. Biotechnol. 4, 175–183 (2011).

    PubMed  PubMed Central  Google Scholar 

  120. 120.

    Patin, N. V., Floros, D. J., Hughes, C. C., Dorrestein, P. C. & Jensen, P. R. The role of inter-species interactions in Salinispora specialized metabolism. Microbiology 164, 946–955 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Ezaki, M. et al. Biphenomycin A production by a mixed culture. Appl. Environ. Microbiol. 58, 3879–3882 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Kurosawa, K. et al. Rhodostreptomycins, antibiotics biosynthesized following horizontal gene transfer from Streptomyces padanus to Rhodococcus fascians. J. Am. Chem. Soc. 130, 1126–1127 (2008).

    CAS  PubMed  Google Scholar 

  123. 123.

    Traxler, M. F., Seyedsayamdost, M. R., Clardy, J. & Kolter, R. Interspecies modulation of bacterial development through iron competition and siderophore piracy. Mol. Microbiol. 86, 628–644 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Onaka, H., Tabata, H., Igarashi, Y., Sato, Y. & Furumai, T. Goadsporin, a chemical substance which promotes secondary metabolism and morphogenesis in streptomycetes. I. Purification and characterization. J. Antibiot. 54, 1036–1044 (2001).

    CAS  PubMed  Google Scholar 

  125. 125.

    Yang, Y. L., Xu, Y., Straight, P. & Dorrestein, P. C. Translating metabolic exchange with imaging mass spectrometry. Nat. Chem. Biol. 5, 885–887 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Mendes, R. et al. Deciphering the rhizosphere microbiome for disease-suppressive bacteria. Science 332, 1097–1100 (2011).

    CAS  PubMed  Google Scholar 

  127. 127.

    Currie, C. R., Scott, J. A., Summerbell, R. C. & Malloch, D. D. Fungus-growing ants use antibiotic-producing bacteria to control garden parasites. Nature 398, 701–704 (1999).

    CAS  Google Scholar 

  128. 128.

    Heine, D. et al. Chemical warfare between leafcutter ant symbionts and a co-evolved pathogen. Nat. Commun. 9, 2208 (2018). This work describes how Pseudonocardia, which protects a fungal garden against infection by a pathogenic fungus, elicits the production of counteracting antibiotics by the pathogen.

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Spaepen, S. in Principles of Plant–Microbe Interactions (ed. Lugtenberg, B.) 247–256 (Springer, 2015).

  130. 130.

    van der Meij, A. et al. Inter- and intracellular colonization of Arabidopsis roots by endophytic Actinobacteria and the impact of plant hormones on their antimicrobial activity. Antonie Van. Leeuwenhoek 111, 679–690 (2018). This study describes the interaction between plants and streptomycetes, and the chemical interaction through which plants might influence specialized metabolite production by endophytic Actinobacteria.

    PubMed  PubMed Central  Google Scholar 

  131. 131.

    Blin, K. et al. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 47, W81–W87 (2019). This work describes a computational tool used by researchers worldwide to predict biosynthetic gene clusters from genome sequences.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    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). PRISM3 predicts various potential chemical products of biosynthetic gene clusters, demonstrating how the field is moving towards natural product structure prediction from a genomic sequence.

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Kautsar, S. A. et al. MIBiG 2.0: a repository for biosynthetic gene clusters of known function. Nucleic Acids Res. 48, D454–D458 (2019).

    PubMed Central  Google Scholar 

  134. 134.

    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). This work shows how GCF classification can be used to mine large data sets for biosynthetic potential.

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Alanjary, M. et al. The Antibiotic Resistant Target Seeker (ARTS), an exploration engine for antibiotic cluster prioritization and novel drug target discovery. Nucleic Acids Res. 45, W42–W48 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Schorn, M. A. et al. Sequencing rare marine actinomycete genomes reveals high density of unique natural product biosynthetic gene clusters. Microbiology 162, 2075–2086 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Charlop-Powers, Z. et al. Global biogeographic sampling of bacterial secondary metabolism. eLife 4, e05048 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. 138.

    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).

    CAS  PubMed  Google Scholar 

  139. 139.

    Tiwari, K. & Gupta, R. K. Rare actinomycetes: a potential storehouse for novel antibiotics. Crit. Rev. Biotechnol. 32, 108–132 (2012).

    CAS  PubMed  Google Scholar 

  140. 140.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    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). This work shows how genome engineering of Actinobacteria by removing genes for common antibiotics may result in the production of novel metabolites that previously remained unidentified.

    CAS  PubMed  Google Scholar 

  142. 142.

    Hiard, S. et al. PREDetector: a new tool to identify regulatory elements in bacterial genomes. Biochem. Biophys. Res. Commun. 357, 861–864 (2007).

    CAS  PubMed  Google Scholar 

  143. 143.

    Tan, K., Moreno-Hagelsieb, G., Collado-Vides, J. & Stormo, G. D. A comparative genomics approach to prediction of new members of regulons. Genome Res. 11, 566–584 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Rigali, S., Anderssen, S., Naome, A. & van Wezel, G. P. Cracking the regulatory code of biosynthetic gene clusters as a strategy for natural product discovery. Biochem. Pharmacol. 153, 24–34 (2018).

    CAS  PubMed  Google Scholar 

  145. 145.

    Carrion, V. J. et al. Pathogen-induced activation of disease-suppressive functions in the endophytic root microbiome. Science 366, 606–612 (2019).

    CAS  PubMed  Google Scholar 

  146. 146.

    Duhrkop, K., Shen, H., Meusel, M., Rousu, J. & Bocker, S. Searching molecular structure databases with tandem mass spectra using CSI:FingerID. Proc. Natl Acad. Sci. USA 112, 12580–12585 (2015).

    PubMed  Google Scholar 

  147. 147.

    van der Hooft, J. J., Wandy, J., Barrett, M. P., Burgess, K. E. & Rogers, S. Topic modeling for untargeted substructure exploration in metabolomics. Proc. Natl Acad. Sci. USA 113, 13738–13743 (2016).

    PubMed  Google Scholar 

  148. 148.

    Mohimani, H. et al. Dereplication of peptidic natural products through database search of mass spectra. Nat. Chem. Biol. 13, 30–37 (2017).

    CAS  PubMed  Google Scholar 

  149. 149.

    Mohimani, H. et al. Dereplication of microbial metabolites through database search of mass spectra. Nat. Commun. 9, 4035 (2018).

    PubMed  PubMed Central  Google Scholar 

  150. 150.

    Ernst, M. et al. MolNetEnhancer: enhanced molecular networks by integrating metabolome mining and annotation tools. Metabolites 9, 144 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Wilson, M. C. & Piel, J. Metagenomic approaches for exploiting uncultivated bacteria as a resource for novel biosynthetic enzymology. Chem. Biol. 20, 636–647 (2013).

    CAS  PubMed  Google Scholar 

  152. 152.

    Smanski, M. J. et al. Synthetic biology to access and expand nature’s chemical diversity. Nat. Rev. Microbiol. 14, 135–149 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Sugimoto, Y. et al. A metagenomic strategy for harnessing the chemical repertoire of the human microbiome. Science 366, eaax9176 (2019). This paper describes an innovative strategy to identify and characterize biosynthetic gene clusters from uncultivated microbes using metagenomics.

    CAS  PubMed  Google Scholar 

  154. 154.

    Smanski, M. J. et al. Functional optimization of gene clusters by combinatorial design and assembly. Nat. Biotechnol. 32, 1241–1249 (2014).

    CAS  PubMed  Google Scholar 

  155. 155.

    Shomar, H. et al. Metabolic engineering of a carbapenem antibiotic synthesis pathway in Escherichia coli. Nat. Chem. Biol. 14, 794–800 (2018).

    CAS  PubMed  Google Scholar 

  156. 156.

    Amos, G. C. A. et al. Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality. Proc. Natl Acad. Sci. USA 114, E11121–E11130 (2017).

    CAS  PubMed  Google Scholar 

  157. 157.

    Machado, H., Tuttle, R. N. & Jensen, P. R. Omics-based natural product discovery and the lexicon of genome mining. Curr. Opin. Microbiol. 39, 136–142 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Badri, D. V. & Vivanco, J. M. Regulation and function of root exudates. Plant. Cell Env. 32, 666–681 (2009).

    CAS  Google Scholar 

  159. 159.

    Badri, D. V., Chaparro, J. M., Zhang, R., Shen, Q. & Vivanco, J. M. Application of natural blends of phytochemicals derived from the root exudates of Arabidopsis to the soil reveal that phenolic-related compounds predominantly modulate the soil microbiome. J. Biol. Chem. 288, 4502–4512 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Bulgarelli, D. et al. Revealing structure and assembly cues for Arabidopsis root-inhabiting bacterial microbiota. Nature 488, 91–95 (2012).

    CAS  PubMed  Google Scholar 

  161. 161.

    Lebeis, S. L. et al. Salicylic acid modulates colonization of the root microbiome by specific bacterial taxa. Science 349, 860–864 (2015).

    CAS  PubMed  Google Scholar 

  162. 162.

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

    CAS  PubMed  Google Scholar 

  163. 163.

    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).

    PubMed  PubMed Central  Google Scholar 

  164. 164.

    Du, C. & van Wezel, G. P. Mining for microbial gems: integrating proteomics in the postgenomic natural product discovery pipeline. Proteomics 18, e1700332 (2018).

    PubMed  Google Scholar 

  165. 165.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Soldatou, S., Eldjarn, G. H., Huerta-Uribe, A., Rogers, S. & Duncan, K. R. Linking biosynthetic and chemical space to accelerate microbial secondary metabolite discovery. FEMS Microbiol. Lett. 366, fnz142 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 180, 688–702 (2020).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by NACTAR grant 16440 from the Netherlands Organization for Scientific Research (NWO) to M.H.M. and G.P.v.W., and by the Profile area ‘Antibiotics’ of the Faculty of Sciences of Leiden University.

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The authors contributed equally to all aspects of the article.

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Correspondence to Marnix H. Medema or Gilles P. van Wezel.

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M.H.M is a member of the Scientific Advisory Board of Hexagon Bio and co-founder of Design Pharmaceuticals. G.P.v.W. is in a committee for the Dutch Ministry of Health. D.A.v.B and B.R.T. do not declare any competing financial interests.

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Glossary

Siderophores

Chelating specialized metabolites produced by bacteria and fungi, which form a soluble complex with iron and thereby facilitate the uptake of this essential element.

Endospore

A dormant, non-reproductive structure that can survive for long periods of time and is important for dispersal of the organism in the environment.

Programmed cell death

(PCD). A cellular suicide mechanism found in eukaryotes and prokaryotes that is activated in response to different stimuli, including biotic and abiotic stresses.

Vegetative hyphae

Long filamentous cells with multiple chromosomes that grow by tip extension and branching, forming a dense network into the surrounding substrate (often referred to as the vegetative or substrate mycelium).

Sporogenic aerial hyphae

Reproductive hyphal structures that emerge from the vegetative mycelium into the air and develop into chains of unigenomic spores.

Saprophytic bacteria

Bacteria, often found in the soil, that feed on dead and decaying organic material.

Prodiginines

A family of red-pigmented, bacterial, specialized metabolites with a wide range of biological activities, including antibacterial, antitumour and immunosuppressive properties.

Actinorhodin

A blue-pigmented polyketide antibiotic that is a model for polyketide biosynthesis.

Ectoines

Bacterial specialized metabolites that act as osmolytes and protect against osmotic stress induced by, for example, changes in salt concentration of the environment.

Terpenes

A class of specialized metabolites produced by plants, fungi and bacteria with different biological activities, often volatile and with a strong odour.

Rhizosphere

The region of the soil and its microbial community immediately surrounding the plant root, which is directly influenced by root exudates.

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van Bergeijk, D.A., Terlouw, B.R., Medema, M.H. et al. Ecology and genomics of Actinobacteria: new concepts for natural product discovery. Nat Rev Microbiol 18, 546–558 (2020). https://doi.org/10.1038/s41579-020-0379-y

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