Skip to main content
SpringerLink
Log in

Engineering Heterologous Hosts for the Enhanced Production of Non-ribosomal Peptides

  • Review Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Non-ribosomal peptides (NRPs) are a family of secondary metabolites with the highest number among entire secondary metabolite types. They are biosynthesized by a multi-modular enzyme complex called non-ribosomal peptide synthetase (NRPS), which is encoded by a biosynthetic gene cluster (BGC) in plants and a special group of microorganisms. NRPs are structurally and functionally diverse with numerous industrial applications. However, native producers of these valuable NRPs have several biotechnological limitations for efficient production, including their slow growth, inefficient genetic manipulations, and silent BGCs. Heterologous expression of NRPS can address these challenges, especially using an array of model organisms with well-studied metabolic networks and readily available genetic engineering tools. Here, we review the applications of representative bacterial heterologous hosts, namely representative model Streptomyces species, Escherichia coli, Pseudomonas putida, and Bacillus subtilis, which have been engineered for the enhanced production of NRPs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kinghorn, A. D., Y. W. Chin, and S. M. Swanson (2009) Discovery of natural product anticancer agents from biodiverse organisms. Curr. Opin. Drug Discov. Devel 12: 189–196.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bohlin, L., U. Goransson, C. Alsmark, C. Weden, and A. Backlund (2010) Natural products in modern life science. Phytochem. Rev. 9: 279–301.

    Article  CAS  Google Scholar 

  3. Grünewald, J. and M. A. Marahiel (2013) Nonribosomal peptide synthesis. pp. 138–149. In: A. J. Kastin (ed.). Handbook of Biologically Active Peptides. Elsevier/AP, Amsterdam, Netherlands.

    Chapter  Google Scholar 

  4. Medema, M. H., R. Kottmann, P. Yilmaz, M. Cummings, J. B. Biggins, K. Blin, I. de Bruijn, Y. H. Chooi, J. Claesen, R. C. Coates, P. Cruz-Morales, S. Duddela, S. Dusterhus, D. J. Edwards, D. P. Fewer, N. Garg, C. Geiger, J. P. Gomez-Escribano, A. Greule, M. Hadjithomas, A. S. Haines, E. J. N. Helfrich, M. L. Hillwig, K. Ishida, A. C. Jones, C. S. Jones, K. Jungmann, C. Kegler, H. U. Kim, P. Kotter, D. Krug, J. Masschelein, A. V. Melnik, S. M. Mantovani, E. A. Monroe, M. Moore, N. Moss, H. W. Nutzmann, G. Pan, A. Pati, D. Petras, F. J. Reen, F. Rosconi, Z. Rui, Z. Tian, N. J. Tobias, Y. Tsunematsu, P. Wiemann, E. Wyckoff, X. Yan, G. Yim, F. Yu, Y. Xie, B. Aigle, A. K. Apel, C. J. Balibar, E. P. Balskus, F. Barona-Gomez, A. Bechthold, H. B. Bode, R. Borriss, S. F. Brady, A. A. Brakhage, P. Caffrey, Y. Q. Cheng, J. Clardy, R. J. Cox, R. De Mot, S. Donadio, M. S. Donia, W. A. van der Donk, P. C. Dorrestein, S. Doyle, A. J. Driessen, M. Ehling-Schulz, K. D. Entian, M. A. Fischbach, L. Gerwick, W. H. Gerwick, H. Gross, B. Gust, C. Hertweck, M. Hofte, S. E. Jensen, J. Ju, L. Katz, L. Kaysser, J. L. Klassen, N. P. Keller, J. Kormanec, O. P. Kuipers, T. Kuzuyama, N. C. Kyrpides, H. J. Kwon, S. Lautru, R. Lavigne, C. Y. Lee, B. Linquan, X. Liu, W. Liu, A. Luzhetskyy, T. Mahmud, Y. Mast, C. Mendez, M. Metsa-Ketela, J. Micklefield, D. A. Mitchell, B. S. Moore, L. M. Moreira, R. Muller, B. A. Neilan, M. Nett, J. Nielsen, F. O'Gara, H. Oikawa, A. Osbourn, M. S. Osburne, B. Ostash, S. M. Payne, J. L. Pernodet, M. Petricek, J. Piel, O. Ploux, J. M. Raaijmakers, J. A. Salas, E. K. Schmitt, B. Scott, R. F. Seipke, B. Shen, D. H. Sherman, K. Sivonen, M. J. Smanski, M. Sosio, E. Stegmann, R. D. Sussmuth, K. Tahlan, C. M. Thomas, Y. Tang, A. W. Truman, M. Viaud, J. D. Walton, C. T. Walsh, T. Weber, G. P. van Wezel, B. Wilkinson, J. M. Willey, W. Wohlleben, G. D. Wright, N. Ziemert, C. Zhang, S. B. Zotchev, R. Breitling, E. Takano, and F. O. Glockner (2015) Minimum information about a biosynthetic gene cluster. Nat. Chem. Biol. 11: 625–631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kishimoto, S., Y. Tsunematsu, M. Sato, and K. Watanabe (2017) Elucidation of biosynthetic pathways of natural products. Chem. Rec. 17: 1095–1108.

    Article  CAS  PubMed  Google Scholar 

  6. Scott, T. A. and J. Piel (2019) The hidden enzymology of bacterial natural product biosynthesis. Nat. Rev. Chem. 3: 404–425.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Weissman, K. J. and P. F. Leadlay (2005) Combinatorial biosynthesis of reduced polyketides. Nat. Rev. Microbiol. 3: 925–936.

    Article  CAS  PubMed  Google Scholar 

  8. Martínez-Núñez, M. A. and V. E. L. y. López (2016) Nonribosomal peptides synthetases and their applications in industry. Sustain. Chem. Process.V. E. L. y. López 4: 13.

    Article  CAS  Google Scholar 

  9. Walsh, C. T., R. V. O'Brien, and C. Khosla (2013) Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. Angew. Chem. Int. Ed. Engl. 52: 7098–7124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, H., D. P. Fewer, L. Holm, L. Rouhiainen, and K. Sivonen (2014) Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes. Proc. Natl. Acad. Sci. U S A. 111: 9259–9264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Blin, K., V. Pascal Andreu, E. L. C. de Los Santos, F. Del Carratore, S. Y. Lee, M. H. Medema, and T. Weber (2019) The antiSMASH database version 2: a comprehensive resource on secondary metabolite biosynthetic gene clusters. Nucleic Acids Res. 47: D625–D630.

    Article  CAS  PubMed  Google Scholar 

  12. Flissi, A., E. Ricart, C. Campart, M. Chevalier, Y. Dufresne, J. Michalik, P. Jacques, C. Flahaut, F. Lisacek, V. Leclere, and M. Pupin (2020) Norine: Update of the nonribosomal peptide resource. Nucleic Acids Res. 48: D465–D469.

    CAS  PubMed  Google Scholar 

  13. Cochrane, S. A. and J. C. Vederas (2016) Lipopeptides from Bacillus and Paenibacillus spp.: A gold mine of antibiotic candidates. Med. Res. Rev. 36: 4–31.

    Article  CAS  PubMed  Google Scholar 

  14. He, S., Y. Ni, L. Lu, Q. Chai, T. Yu, Z. Shen, and C. Yang (2020) Simultaneous degradation of n-hexane and production of biosurfactants by Pseudomonas sp. strain NEE2 isolated from oil-contaminated soils. Chemosphere. 242: 125237.

    Article  CAS  PubMed  Google Scholar 

  15. Le, V. H., M. Inai, R. M. Williams, and T. Kan (2015) Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. Nat. Prod. Rep. 32: 328–347.

    CAS  PubMed  Google Scholar 

  16. Petit, K. and J. F. Biard (2013) Marine natural products and related compounds as anticancer agents: an overview of their clinical status. Anticancer Agents Med. Chem. 13: 603–631.

    Article  CAS  PubMed  Google Scholar 

  17. Drake, E. J., B. R. Miller, C. Shi, J. T. Tarrasch, J. A. Sundlov, C. L. Allen, G. Skiniotis, C. C. Aldrich, and A. M. Gulick (2016) Structures of two distinct conformations of holo-nonribosomal peptide synthetases. Nature. 529: 235–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Finking, R. and M. A. Marahiel (2004) Biosynthesis of nonribosomal peptides. Annu. Rev. Microbiol. 58: 453–488.

    Article  CAS  PubMed  Google Scholar 

  19. Miller, B. R. and A. M. Gulick (2016) Structural biology of nonribosomal peptide synthetases. Methods. Mol. Biol. 1401: 3–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bloudoff, K. and T. M. Schmeing (2017) Structural and functional aspects of the nonribosomal peptide synthetase condensation domain superfamily: Discovery, dissection and diversity. Biochim. Biophys. Acta. Proteins Proteom. 1865: 1587–1604.

    Article  CAS  PubMed  Google Scholar 

  21. Wenzel, S. C. and R. Muller (2005) Recent developments towards the heterologous expression of complex bacterial natural product biosynthetic pathways. Curr. Opin. Biotechnol. 16: 594–606.

    Article  CAS  PubMed  Google Scholar 

  22. Bekiesch, P., P. Basitta, and A. K. Apel (2016) Challenges in the heterologous production of antibiotics in Streptomyces. Arch. Pharm. (Weinheim). 349: 594–601.

    Article  CAS  PubMed  Google Scholar 

  23. Gomez-Escribano, J. P. and M. J. Bibb (2012) Streptomyces coelicolor as an expression host for heterologous gene clusters. Methods Enzymol. 517: 279–300.

    Article  CAS  PubMed  Google Scholar 

  24. Galm, U. and B. Shen (2006) Expression of biosynthetic gene clusters in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opin. Drug Discov. 1: 409–437.

    Article  CAS  PubMed  Google Scholar 

  25. Ongley, S. E., X. Bian, B. A. Neilan, and R. Muller (2013) Recent advances in the heterologous expression of microbial natural product biosynthetic pathways. Nat. Prod. Rep. 30: 1121–1138.

    Article  CAS  PubMed  Google Scholar 

  26. Weber, T., P. Charusanti, E. M. Musiol-Kroll, X. Jiang, Y. Tong, H. U. Kim, and S. Y. Lee (2015) Metabolic engineering of antibiotic factories: New tools for antibiotic production in actinomycetes. Trends Biotechnol. 33: 15–26.

    Article  CAS  PubMed  Google Scholar 

  27. Nah, H. J., H. R. Pyeon, S. H. Kang, S. S. Choi, and E. S. Kim (2017) Cloning and heterologous expression of a large-sized natural product biosynthetic gene cluster in Streptomyces Species. Front. Microbiol. 8: 394.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Zhang, M. M., Y. Wang, E. L. Ang, and H. Zhao (2016) Engineering microbial hosts for production of bacterial natural products. Nat. Prod. Rep. 33: 963–987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nepal, K. K. and G. Wang (2019) Streptomycetes: Surrogate hosts for the genetic manipulation of biosynthetic gene clusters and production of natural products. Biotechnol. Adv. 37: 1–20.

    Article  CAS  PubMed  Google Scholar 

  30. Myronovskyi, M. and A. Luzhetskyy (2019) Heterologous production of small molecules in the optimized Streptomyces hosts. Nat. Prod. Rep. 36: 1281–1294.

    Article  CAS  PubMed  Google Scholar 

  31. Vassaux, A., L. Meunier, M. Vandenbol, D. Baurain, P. Fickers, P. Jacques, and V. Leclere (2019) Nonribosomal peptides in fungal cell factories: From genome mining to optimized heterologous production. Biotechnol. Adv. 37: 107449.

    Article  CAS  PubMed  Google Scholar 

  32. Bentley, S. D., K. F. Chater, A. M. Cerdeno-Tarraga, G. L. Challis, N. R. Thomson, K. D. James, D. E. Harris, M. A. Quail, H. Kieser, D. Harper, A. Bateman, S. Brown, G. Chandra, C. W. Chen, M. Collins, A. Cronin, A. Fraser, A. Goble, J. Hidalgo, T. Hornsby, S. Howarth, C. H. Huang, T. Kieser, L. Larke, L. Murphy, K. Oliver, S. O'Neil, E. Rabbinowitsch, M. A. Rajandream, K. Rutherford, S. Rutter, K. Seeger, D. Saunders, S. Sharp, R. Squares, S. Squares, K. Taylor, T. Warren, A. Wietzorrek, J. Woodward, B. G. Barrell, J. Parkhill, and D. A. Hopwood (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature. 417: 141–147.

    Article  PubMed  Google Scholar 

  33. Tong, Y., H. L. Robertsen, K. Blin, T. Weber, and S. Y. Lee (2018) CRISPR-Cas9 toolkit for actinomycete genome editing. Methods Mol. Biol. 1671: 163–184.

    Article  CAS  PubMed  Google Scholar 

  34. Musiol-Kroll, E. M., A. Tocchetti, M. Sosio, and E. Stegmann (2019) Challenges and advances in genetic manipulation of filamentous actinomycetes-the remarkable producers of specialized metabolites. Nat. Prod. Rep. 36: 1351–1369.

    Article  CAS  PubMed  Google Scholar 

  35. Gomez-Escribano, J. P. and M. J. Bibb (2011) Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters. Microb. Biotechnol. 4: 207–215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Okamoto-Hosoya, Y., T. A. Sato, and K. Ochi (2000) Resistance to paromomycin is conferred by rpsL mutations, accompanied by an enhanced antibiotic production in Streptomyces coelicolor A3(2). J. Antibiot. (Tokyo). 53: 1424–1427.

    Article  CAS  Google Scholar 

  37. Hu, H., Q. Zhang, and K. Ochi (2002) Activation of antibiotic biosynthesis by specified mutations in the rpoB gene (encoding the RNA polymerase beta subunit) of Streptomyces lividans. J. Bacteriol. 184: 3984–3991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamanaka, K., K. A. Reynolds, R. D. Kersten, K. S. Ryan, D. J. Gonzalez, V. Nizet, P. C. Dorrestein, and B. S. Moore (2014) Direct cloning and refactoring of a silent lipopeptide biosynthetic gene cluster yields the antibiotic taromycin A. Proc. Natl. Acad. Sci. U S A. 111: 1957–1962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li, Q., Y. Song, X. Qin, X. Zhang, A. Sun, and J. Ju (2015) Identification of the biosynthetic gene cluster for the antiinfective desotamides and production of a new analogue in a heterologous host. J. Nat. Prod. 78: 944–948.

    Article  CAS  PubMed  Google Scholar 

  40. Leipoldt, F., J. Santos-Aberturas, D. P. Stegmann, F. Wolf, A. Kulik, R. Lacret, D. Popadic, D. Keinhorster, N. Kirchner, P. Bekiesch, H. Gross, A. W. Truman, and L. Kaysser (2017) Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors. Nat. Commun. 8: 1965.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Ruckert, C., A. Albersmeier, T. Busche, S. Jaenicke, A. Winkler, O. H. Friethjonsson, G. O. Hreggviethsson, C. Lambert, D. Badcock, K. Bernaerts, J. Anne, A. Economou, and J. Kalinowski (2015) Complete genome sequence of Streptomyces lividans TK24. J. Biotechnol. 199: 21–22.

    Article  PubMed  CAS  Google Scholar 

  42. Baltz, R. H. (2010) Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J. Ind. Microbiol. Biotechnol. 37: 759–772.

    Article  CAS  PubMed  Google Scholar 

  43. Meschke, H., S. Walter, and H. Schrempf (2012) Characterization and localization of prodiginines from Streptomyces lividans suppressing Verticillium dahliae in the absence or presence of Arabidopsis thaliana. Environ. Microbiol. 14: 940–952.

    Article  CAS  PubMed  Google Scholar 

  44. Shi, J., Y. J. Zeng, B. Zhang, F. L. Shao, Y. C. Chen, X. Xu, Y. Sun, Q. Xu, R. X. Tan, and H. M. Ge (2019) Comparative genome mining and heterologous expression of an orphan NRPS gene cluster direct the production of ashimides. Chem. Sci. 10: 3042–3048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Weber, T., K. Blin, S. Duddela, D. Krug, H. U. Kim, R. Bruccoleri, S. Y. Lee, M. A. Fischbach, R. Muller, W. Wohlleben, R. Breitling, E. Takano, and M. H. Medema (2015) antiSMASH 3.0-a comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Res. 43: W237–W243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ahmed, Y., Y. Rebets, M. R. Estevez, J. Zapp, M. Myronovskyi, and A. Luzhetskyy (2020) Engineering of Streptomyces lividans for heterologous expression of secondary metabolite gene clusters. Microb. Cell Fact. 19: 5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Parkinson, E. I., J. H. Tryon, A. W. Goering, K. S. Ju, R. A. McClure, J. D. Kemball, S. Zhukovsky, D. P. Labeda, R. J. Thomson, N. L. Kelleher, and W. W. Metcalf (2018) Discovery of the tyrobetaine natural products and their biosynthetic gene cluster via metabologenomics. ACS Chem. Biol. 13: 1029–1037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. McClure, R. A., A. W. Goering, K. S. Ju, J. A. Baccile, F. C. Schroeder, W. W. Metcalf, R. J. Thomson, and N. L. Kelleher (2016) Elucidating the rimosamide-detoxin natural product families and their biosynthesis using metabolite/gene cluster correlations. ACS Chem. Biol. 11: 3452–3460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miao, V., M. F. Coeffet-LeGal, P. Brian, R. Brost, J. Penn, A. Whiting, S. Martin, R. Ford, I. Parr, M. Bouchard, C. J. Silva, S. K. Wrigley, and R. H. Baltz (2005) Daptomycin biosynthesis in Streptomyces roseosporus: Cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology. 151: 1507–1523.

    Article  CAS  PubMed  Google Scholar 

  50. Felnagle, E. A., M. R. Rondon, A. D. Berti, H. A. Crosby, and M. G. Thomas (2007) Identification of the biosynthetic gene cluster and an additional gene for resistance to the antituberculosis drug capreomycin. Appl. Environ. Microbiol. 73: 4162–4170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Barkei, J. J., B. M. Kevany, E. A. Felnagle, and M. G. Thomas (2009) Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans. Chembiochem. 10: 366–376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jian, X. H., H. X. Pan, T. T. Ning, Y. Y. Shi, Y. S. Chen, Y. Li, X. W. Zeng, J. Xu, and G. L. Tang (2012) Analysis of YM-216391 biosynthetic gene cluster and improvement of the cyclopeptide production in a heterologous host. ACS Chem. Biol. 7: 646–651.

    Article  CAS  PubMed  Google Scholar 

  53. Blodgett, J. A. V., J. K. Zhang, and W. W. Metcalf (2005) Molecular cloning, sequence analysis, and heterologous expression of the phosphinothricin tripeptide biosynthetic gene cluster from Streptomyces viridochromogenes DSM 40736. Antimicrob. Agents. Chemother. 49: 230–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Rui, Z., W. Huang, F. Xu, M. Han, X. Liu, S. Lin, and W. Zhang (2015) Sparsomycin biosynthesis highlights unusual module architecture and processing mechanism in non-ribosomal peptide synthetase. ACS Chem. Biol. 10: 1765–1769.

    Article  CAS  PubMed  Google Scholar 

  55. Zaburannyi, N., M. Rabyk, B. Ostash, V. Fedorenko, and A. Luzhetskyy (2014) Insights into naturally minimised Streptomyces albus J1074 genome. BMC Genomics. 15: 97.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lombo, F., A. Velasco, A. Castro, F. de la Calle, A. F. Brana, J. M. Sanchez-Puelles, C. Mendez, and J. A. Salas (2006) Deciphering the biosynthesis pathway of the antitumor thiocoraline from a marine actinomycete and its expression in two Streptomyces species. Chembiochem. 7: 366–376.

    Article  CAS  PubMed  Google Scholar 

  57. Schorn, M., J. Zettler, J. P. Noel, P. C. Dorrestein, B. S. Moore, and L. Kaysser (2014) Genetic basis for the biosynthesis of the pharmaceutically important class of epoxyketone proteasome inhibitors. ACS Chem. Biol. 9: 301–309.

    Article  CAS  PubMed  Google Scholar 

  58. Skyrud, W., J. Liu, D. Thankachan, M. Cabrera, R. F. Seipke, and W. Zhang (2018) Biosynthesis of the 15-membered ring depsipeptide neoantimycin. ACS Chem. Biol. 13: 1398–1406.

    Article  CAS  PubMed  Google Scholar 

  59. Hover, B. M., S. H. Kim, M. Katz, Z. Charlop-Powers, J. G. Owen, M. A. Ternei, J. Maniko, A. B. Estrela, H. Molina, S. Park, D. S. Perlin, and S. F. Brady (2018) Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens. Nat. Microbiol. 3: 415–422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, H., L. Fang, M. S. Osburne, and B. A. Pfeifer (2016) The continuing development of E. coli as a heterologous host for complex natural product biosynthesis. Methods Mol. Biol. 1401: 121–134.

    Article  CAS  PubMed  Google Scholar 

  61. Pontrelli, S., T. Y. Chiu, E. I. Lan, F. Y. H. Chen, P. Chang, and J. C. Liao (2018) Escherichia coli as a host for metabolic engineering. Metab. Eng. 50: 16–46.

    Article  CAS  PubMed  Google Scholar 

  62. Choi, K. R., J. H. Shin, J. S. Cho, D. Yang, and S. Y. Lee (2016) Systems metabolic engineering of Escherichia coli. EcoSal Plus..doi:https://doi.org/10.1128/ecosalplus.ESP-0010-2015.

    Google Scholar 

  63. Yang, D., S. Y. Park, Y. S. Park, H. Eun, and S. Y. Lee (2020) Metabolic engineering of Escherichia coli for natural product biosynthesis. Trends Biotechnol. 38: 745–765.

    Article  CAS  PubMed  Google Scholar 

  64. Owen, J. G., J. N. Copp, and D. F. Ackerley (2011) Rapid and flexible biochemical assays for evaluating 4'-phosphopantetheinyl transferase activity. Biochem. J. 436: 709–717.

    Article  CAS  PubMed  Google Scholar 

  65. Pfeifer, B. A., S. J. Admiraal, H. Gramajo, D. E. Cane, and C. Khosla (2001) Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli.. Science. 291: 1790–1792.

    Article  CAS  PubMed  Google Scholar 

  66. Greunke, C., E. R. Duell, P. M. D'Agostino, A. Glockle, K. Lamm, and T. A. M. Gulder (2018) Direct Pathway Cloning (DiPaC) to unlock natural product biosynthetic potential. Metab. Eng. 47: 334–345.

    Article  CAS  PubMed  Google Scholar 

  67. Fu, J., X. Bian, S. Hu, H. Wang, F. Huang, P. M. Seibert, A. Plaza, L. Xia, R. Muller, A. F. Stewart, and Y. Zhang (2012) Full-length RecE enhances linear-linear homologous recombination and facilitates direct cloning for bioprospecting. Nat. Biotechnol. 30: 440–446.

    Article  CAS  PubMed  Google Scholar 

  68. Yu, D., F. Xu, J. Valiente, S. Wang, and J. Zhan (2013) An indigoidine biosynthetic gene cluster from Streptomyces chromofuscus ATCC 49982 contains an unusual IndB homologue. J. Ind. Microbiol. Biotechnol. 40: 159–168.

    Article  CAS  PubMed  Google Scholar 

  69. Xu, F., D. Gage, and J. Zhan (2015) Efficient production of indigoidine in Escherichia coli. J. Ind. Microbiol. Biotechnol. 42: 1149–1155.

    Article  CAS  PubMed  Google Scholar 

  70. Murli, S., J. Kennedy, L. C. Dayem, J. R. Carney, and J. T. Kealey (2003) Metabolic engineering of Escherichia coli for improved 6-deoxyerythronolide B production. J. Ind. Microbiol. Biotechnol. 30: 500–509.

    Article  CAS  PubMed  Google Scholar 

  71. Pfeifer, B. A., C. C. C. Wang, C. T. Walsh, and C. Khosla (2003) Biosynthesis of yersiniabactin, a complex polyketidenonribosomal peptide, using Escherichia coli as a heterologous host. Appl. Environ. Microbiol. 69: 6698–6702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ahmadi, M. K. and B. A. Pfeifer (2016) Improved heterologous production of the nonribosomal peptide-polyketide siderophore yersiniabactin through metabolic engineering and induction optimization. Biotechnol. Prog. 32: 1412–1417.

    Article  CAS  PubMed  Google Scholar 

  73. Mutka, S. C., J. R. Carney, Y. Liu, and J. Kennedy (2006) Heterologous production of epothilone C and D in Escherichia coli. Biochemistry. 45: 1321–1330.

    Article  CAS  PubMed  Google Scholar 

  74. Bian, X., F. Huang, H. Wang, T. Klefisch, R. Muller, and Y. Zhang (2014) Heterologous production of glidobactins/luminmycins in Escherichia coli Nissle containing the glidobactin biosynthetic gene cluster from Burkholderia DSM7029. Chembiochem. 15: 2221–2224.

    Article  CAS  PubMed  Google Scholar 

  75. Gaitatzis, N., A. Hans, R. Muller, and S. Beyer (2001) The mtaA gene of the myxothiazol biosynthetic gene cluster from Stigmatella aurantiaca DW4/3-1 encodes a phosphopantetheinyl transferase that activates polyketide synthases and polypeptide synthetases. J. Biochem. 129: 119–124.

    Article  CAS  PubMed  Google Scholar 

  76. Ongley, S. E., X. Bian, Y. Zhang, R. Chau, W. H. Gerwick, R. Muller, and B. A. Neilan (2013) High-titer heterologous production in E. coli of lyngbyatoxin, a protein kinase C activator from an uncultured marine cyanobacterium. ACS Chem. Biol. 8: 1888–1893.

    Article  CAS  PubMed  Google Scholar 

  77. Bian, X., F. Huang, F. A. Stewart, L. Xia, Y. Zhang, and R. Muller (2012) Direct cloning, genetic engineering, and heterologous expression of the syringolin biosynthetic gene cluster in E. coli through Red/ET recombineering. Chembiochem. 13: 1946–1952.

    Article  CAS  PubMed  Google Scholar 

  78. Tang, Y., S. Frewert, K. Harmrolfs, J. Herrmann, L. Karmann, U. Kazmaier, L. Xia, Y. Zhang, and R. Muller (2015) Heterologous expression of an orphan NRPS gene cluster from Paenibacillus larvae in Escherichia coli revealed production of sevadicin. J. Biotechnol. 194: 112–114.

    Article  CAS  PubMed  Google Scholar 

  79. Nikel, P. I., M. Chavarria, A. Danchin, and V. de Lorenzo (2016) From dirt to industrial applications: Pseudomonas putida as a synthetic biology chassis for hosting harsh biochemical reactions. Curr. Opin. Chem. Biol. 34: 20–29.

    Article  CAS  PubMed  Google Scholar 

  80. Loeschcke, A. and S. Thies (2015) Pseudomonas putida-a versatile host for the production of natural products. Appl. Microbiol. Biotechnol. 99: 6197–6214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Ricaurte, D. E., E. Martinez-Garcia, A. Nyerges, C. Pal, V. de Lorenzo, and T. Aparicio (2018) A standardized workflow for surveying recombinases expands bacterial genome-editing capabilities. Microb. Biotechnol. 11: 176–188.

    Article  CAS  PubMed  Google Scholar 

  82. Domrose, A., J. Hage-Hulsmann, S. Thies, R. Weihmann, L. Kruse, M. Otto, N. Wierckx, K. E. Jaeger, T. Drepper, and A. Loeschcke (2019) Pseudomonas putida rDNA is a favored site for the expression of biosynthetic genes. Sci. Rep. 9: 7028.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Li, Y., K. J. Weissman, and R. Muller (2010) Insights into multienzyme docking in hybrid PKS-NRPS megasynthetases revealed by heterologous expression and genetic engineering. Chembiochem. 11: 1069–1075.

    Article  CAS  PubMed  Google Scholar 

  84. Wenzel, S. C., F. Gross, Y. Zhang, J. Fu, A. F. Stewart, and R. Muller (2005) Heterologous expression of a myxobacterial natural products assembly line in Pseudomonads via red/ET recombineering. Chem. Biol. 12: 349-356.

  85. Kunst, F., N. Ogasawara, I. Moszer, A. M. Albertini, G. Alloni, V. Azevedo, M. G. Bertero, P. Bessieres, A. Bolotin, S. Borchert, R. Borriss, L. Boursier, A. Brans, M. Braun, S. C. Brignell, S. Bron, S. Brouillet, C. V. Bruschi, B. Caldwell, V. Capuano, N. M. Carter, S. K. Choi, J. J. Cordani, I. F. Connerton, N. J. Cummings, R. A. Daniel, F. Denziot, K. M. Devine, A. Dusterhoft, S. D. Ehrlich, P. T. Emmerson, K. D. Entian, J. Errington, C. Fabret, E. Ferrari, D. Foulger, C. Fritz, M. Fujita, Y. Fujita, S. Fuma, A. Galizzi, N. Galleron, S. Y. Ghim, P. Glaser, A. Goffeau, E. J. Golightly, G. Grandi, G. Guiseppi, B. J. Guy, K. Haga, J. Haiech, C. R. Harwood, A. Henaut, H. Hilbert, S. Holsappel, S. Hosono, M. F. Hullo, M. Itaya, L. Jones, B. Joris, D. Karamata, Y. Kasahara, M. Klaerr-Blanchard, C. Klein, Y. Kobayashi, P. Koetter, G. Koningstein, S. Krogh, M. Kumano, K. Kurita, A. Lapidus, S. Lardinois, J. Lauber, V. Lazarevic, S. M. Lee, A. Levine, H. Liu, S. Masuda, C. Mauel, C. Medigue, N. Medina, R. P. Mellado, M. Mizuno, D. Moestl, S. Nakai, M. Noback, D. Noone, M. O'Reilly, K. Ogawa, A. Ogiwara, B. Oudega, S. H. Park, V. Parro, T. M. Pohl, D. Portelle, S. Porwollik, A. M. Prescott, E. Presecan, P. Pujic, B. Purnelle, G. Rapoport, M. Rey, S. Reynolds, M. Rieger, C. Rivolta, E. Rocha, B. Roche, M. Rose, Y. Sadaie, T. Sato, E. Scanlan, S. Schleich, R. Schroeter, F. Scoffone, J. Sekiguchi, A. Sekowska, S. J. Seror, P. Serror, B. S. Shin, B. Soldo, A. Sorokin, E. Tacconi, T. Takagi, H. Takahashi, K. Takemaru, M. Takeuchi, A. Tamakoshi, T. Tanaka, P. Terpstra, A. Togoni, V. Tosato, S. Uchiyama, M. Vandebol, F. Vannier, A. Vassarotti, A. Viari, R. Wambutt, H. Wedler, T. Weitzenegger, P. Winters, A. Wipat, H. Yamamoto, K. Yamane, K. Yasumoto, K. Yata, K. Yoshida, H. F. Yoshikawa, E. Zumstein, H. Yoshikawa, and A. Danchin (1997) The complete genome sequence of the Gram-positive bacterium Bacillus subtilis. Nature. 390: 249-256.

  86. Itaya, M., K. Tsuge, M. Koizumi, and K. Fujita (2005) Combining two genomes in one cell: Stable cloning of the Synechocystis PCC6803 genome in the Bacillus subtilis 168 genome. Proc. Natl. Acad. Sci. U S A. 102: 15971–15976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kaspar, F., P. Neubauer, and M. Gimpel (2019) Bioactive secondary metabolites from Bacillus subtilis: A comprehensive review. J. Nat. Prod. 82: 2038–2053.

    Article  CAS  PubMed  Google Scholar 

  88. Liu, Q., Q. Shen, X. Bian, H. Chen, J. Fu, H. Wang, P. Lei, Z. Guo, W. Chen, D. Li, and Y. Zhang (2016) Simple and rapid direct cloning and heterologous expression of natural product biosynthetic gene cluster in Bacillus subtilis via Red/ET recombineering. Sci. Rep. 6: 34623.

  89. Eppelmann, K., S. Doekel, and M. A. Marahiel (2001) Engineered biosynthesis of the peptide antibiotic bacitracin in the surrogate host Bacillus subtilis. J. Biol. Chem. 276: 34824–34831.

    Article  CAS  PubMed  Google Scholar 

  90. Choi, S. K., S. Y. Park, R. Kim, S. B. Kim, C. H. Lee, J. F. Kim, and S. H. Park (2009) Identification of a polymyxin synthetase gene cluster of Paenibacillus polymyxa and heterologous expression of the gene in Bacillus subtilis. J. Bacteriol. 191: 3350-3358.

  91. Zobel, S., J. Kumpfmuller, R. D. Sussmuth, and T. Schweder (2015) Bacillus subtilis as heterologous host for the secretory production of the non-ribosomal cyclodepsipeptide enniatin. Appl. Microbiol. Biotechnol. 99: 681-691.

  92. Zeigler, D. R., Z. Pragai, S. Rodriguez, B. Chevreux, A. Muffler, T. Albert, R. Bai, M. Wyss, and J. B. Perkins (2008) The origins of 168, W23, and other Bacillus subtilis legacy strains. J. Bacteriol. 190: 6983–6995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ke, J. and Y. Yoshikuni (2020) Multi-chassis engineering for heterologous production of microbial natural products. Curr. Opin. Biotechnol. 62: 88–97.

    Article  CAS  PubMed  Google Scholar 

  94. Awan, A. R., B. A. Blount, D. J. Bell, W. M. Shaw, J. C. H. Ho, R. M. McKiernan, and T. Ellis (2017) Biosynthesis of the antibiotic nonribosomal peptide penicillin in baker's yeast. Nat. Commun. 8: 15202.

  95. Siewers, V., X. Chen, L. Huang, J. Zhang, and J. Nielsen (2009) Heterologous production of non-ribosomal peptide LLD-ACV in Saccharomyces cerevisiae. Metab. Eng. 11: 391–397.

    Article  CAS  PubMed  Google Scholar 

  96. Kallscheuer, N., H. Kage, L. Milke, M. Nett, and J. Marienhagen (2019) Microbial synthesis of the type I polyketide 6-methylsalicylate with Corynebacterium glutamicum. Appl. Microbiol. Biotechnol. 103: 9619-9631.

  97. Hao, T., Z. Xie, M. Wang, L. Liu, Y. Zhang, W. Wang, Z. Zhang, X. Zhao, P. Li, Z. Guo, S. Gao, C. Lou, G. Zhang, J. Merritt, G. P. Horsman, and Y. Chen (2019) An anaerobic bacterium host system for heterologous expression of natural product biosynthetic gene clusters. Nat. Commun. 10: 3665.

  98. Li, J., Z. Guo, W. Huang, X. Meng, G. Ai, G. Tang, and Y. Chen (2013) Mining of a streptothricin gene cluster from Streptomyces sp. TP-A0356 genome via heterologous expression. Sci. China Life Sci. 56: 619–627.

    Article  CAS  PubMed  Google Scholar 

  99. Luo, Y., H. Huang, J. Liang, M. Wang, L. Lu, Z. Shao, R. E. Cobb, and H. Zhao (2013) Activation and characterization of a cryptic polycyclic tetramate macrolactam biosynthetic gene cluster. Nat. Commun. 4: 2894.

    Article  PubMed  CAS  Google Scholar 

  100. Wyatt, M. A. and N. A. Magarvey (2013) Optimizing dimodular nonribosomal peptide synthetases and natural dipeptides in an Escherichia coli heterologous host. Biochem. Cell Biol. 91: 203–208.

    Article  CAS  PubMed  Google Scholar 

  101. Watanabe, K., K. Hotta, A. P. Praseuth, K. Koketsu, A. Migita, C. N. Boddy, C. C. Wang, H. Oguri, and H. Oikawa (2006) Total biosynthesis of antitumor nonribosomal peptides in Escherichia coli. Nat. Chem. Biol. 2: 423-428.

  102. Yang, C., Y. Xu, K. Xu, G. Tan, and X. Yu (2018) Preparation of new halogenated diphenyl pyrazine analogs in Escherichia coli by a mono-module fungal nonribosomal peptide synthetase from Penicillium herquei. Tetrahedron Lett. 59: 3084-3087.

  103. Praseuth, A. P., M. B. Praseuth, H. Oguri, H. Oikawa, K. Watanabe, and C. C. C. Wang (2008) Improved production of triostin A in engineered Escherichia coli with furnished quinoxaline chromophore by design of experiments in smallscale culture. Biotechnol. Prog. 24: 134–139.

    Article  CAS  PubMed  Google Scholar 

  104. Jaitzig, J., J. Li, R. D. Sussmuth, and P. Neubauer (2014) Reconstituted biosynthesis of the nonribosomal macrolactone antibiotic valinomycin in Escherichia coli. ACS Synth. Biol. 3: 432–438.

    Article  CAS  PubMed  Google Scholar 

  105. Yan, F., D. Auerbach, Y. Chai, L. Keller, Q. Tu, S. Huttel, A. Glemser, H. A. Grab, T. Bach, Y. Zhang, and R. Muller (2018) Biosynthesis and heterologous production of vioprolides: Rational biosynthetic engineering and unprecedented 4-methylazetidinecarboxylic acid formation. Angew. Chem. Int. Ed. Engl. 57: 8754–8759.

    Article  CAS  PubMed  Google Scholar 

  106. Kautsar, S. A., K. Blin, S. Shaw, J. C. Navarro-Munoz, B. R. Terlouw, J. J. J. van der Hooft, J. A. van Santen, V. Tracanna, H. G. Suarez Duran, V. Pascal Andreu, N. Selem-Mojica, M. Alanjary, S. L. Robinson, G. Lund, S. C. Epstein, A. C. Sisto, L. K. Charkoudian, J. Collemare, R. G. Linington, T. Weber, and M. H. Medema (2020) MIBiG 2.0: a repository for biosynthetic gene clusters of known function. Nucleic Acids Res. 48: D454–D458.

    PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Technology Development Program to Solve Climate Changes on Systems Metabolic Engineering for Biorefineries (NRF-2012M1A2A2026556 and NRF-2012M1A2A2026557) from the Ministry of Science and ICT through the National Research Foundation of Korea. This work was also supported by the Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Korean government, the Ministry of Science and ICT (NRF-2018M3A9H3020459).

Author information

Authors and Affiliations

  1. Systems Biology and Medicine Laboratory, Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Korea

    Komal Sharma, Mohammad Rifqi Ghiffary & Hyun Uk Kim

  2. Systems Metabolic Engineering and Systems Healthcare Cross-Generation Collaborative Laboratory, KAIST, Daejeon, 34141, Korea

    Komal Sharma, Mohammad Rifqi Ghiffary, Hyun Uk Kim & Sang Yup Lee

  3. Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering, KAIST Institute for BioCentury, KAIST, Daejeon, 34141, Korea

    Sang Yup Lee

  4. KAIST Institute for Artificial Intelligence, BioProcess Engineering Research Center and BioInformatics Research Center, KAIST, Daejeon, 34141, Korea

    Hyun Uk Kim & Sang Yup Lee

Authors
  1. Komal Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad Rifqi Ghiffary
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hyun Uk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sang Yup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hyun Uk Kim or Sang Yup Lee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, K., Ghiffary, M.R., Kim, H.U. et al. Engineering Heterologous Hosts for the Enhanced Production of Non-ribosomal Peptides. Biotechnol Bioproc E 25, 795–809 (2020). https://doi.org/10.1007/s12257-020-0080-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-020-0080-z

Keywords

Search

Navigation