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Science China Life Sciences

, Volume 60, Issue 9, pp 939–947 | Cite as

Biosynthesis and combinatorial biosynthesis of antifungal nucleoside antibiotics

  • Guoqing Niu
  • Jiazhen Zheng
  • Huarong TanEmail author
Review

Abstract

There is an urgent need for new antifungal agents to treat or combat fungal infection in humans and plants. Antifungal nucleoside antibiotics are an important family of natural products with distinctive structural features. Understanding their biosynthetic machinery is of great importance for the improvement of antibiotics titers. More importantly, it is a requisite for combinatorial biosynthesis to create hybrid nucleoside antibiotics. We herein focus on findings on the natural and designed biosynthesis of this important family of nucleoside antibiotics.

Keywords

nucleoside antibiotics biosynthesis combinatorial biosynthesis 

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Notes

Acknowledgements

This work was supported by grants from the Ministry of Science and Technology of China (2013CB734001) and the National Natural Science Foundation of China (31470206 and 31571281).

References

  1. Binter, A., Oberdorfer, G., Hofzumahaus, S., Nerstheimer, S., Altenbacher, G., Gruber, K., and Macheroux, P. (2011). Characterization of the PLPdependent aminotransferase NikK from Streptomyces tendae and its putative role in nikkomycin biosynthesis. FEBS J 278, 4122–4135.CrossRefPubMedGoogle Scholar
  2. Bormann, C., KÁLmÁNczhelyi, A., SÜßmuth, R., and Jung, G. (1999). Production of nikkomycins Bx and Bz by mutasynthesis with genetically engineered Streptomyces tendae Tu901. J Antibiot 52, 102–108.CrossRefPubMedGoogle Scholar
  3. Bruckner, R.C., Zhao, G., Venci, D., and Jorns, M.S. (2004). Nikkomycin biosynthesis: formation of a 4-electron oxidation product during turnover of NikD with its physiological substrate †. Biochemistry 43, 9160–9167.CrossRefPubMedGoogle Scholar
  4. Bruntner, C., and Bormann, C. (1998). The Streptomyces tendae Tu901 L-lysine 2-aminotransferase catalyzes the initial reaction in nikkomycin D biosynthesis. Eur J Biochem 254, 347–355.CrossRefPubMedGoogle Scholar
  5. Bruntner, C., Lauer, B., Schwarz, W., Mohrle, V., and Bormann, C. (1999). Molecular characterization of co-transcribed genes from Streptomyces tendae Tu901 involved in the biosynthesis of the peptidyl moiety of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 262, 102–114.PubMedGoogle Scholar
  6. Chao, R., Yuan, Y.B., and Zhao, H.M. (2015). Building biological foundries for next-generation synthetic biology. Sci China Life Sci 58, 658–665.CrossRefPubMedGoogle Scholar
  7. Chen, H., Hubbard, B.K., O’Connor, S.E., and Walsh, C.T. (2002). Formation of ß-hydroxy histidine in the biosynthesis of nikkomycin antibiotics. Chem Biol 9, 103–112.CrossRefPubMedGoogle Scholar
  8. Chen, W., Dai, D., Wang, C., Huang, T., Zhai, L., and Deng, Z. (2013). Genetic dissection of the polyoxin building block-carbamoylpolyoxamic acid biosynthesis revealing the “pathway redundancy” in metabolic networks. Microb Cell Fact 12, 121.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen, W., Huang, T., He, X., Meng, Q., You, D., Bai, L., Li, J., Wu, M., Li, R., Xie, Z., Zhou, H., Zhou, X., Tan, H., and Deng, Z. (2009). Characterization of the polyoxin biosynthetic gene cluster fromStreptomyces cacaoi and engineered production of polyoxin H. J Biol Chem 284, 10627–10638.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cone, M.C., Yin, X., Grochowski, L.L., Parker, M.R., and Zabriskie, T.M. (2003). The blasticidin S biosynthesis gene cluster from Streptomyces griseochromogenes: sequence analysis, organization, and initial characterization. ChemBioChem 4, 821–828.CrossRefPubMedGoogle Scholar
  11. Delzer, J., Fiedler, H.P., Müller, H., Zähner, H., Rathmann, R., Ernst, K., and König, W.A. (1984). New nikkomycins by mutasynthesis and directed fermentation. J Antibiot 37, 80–82.CrossRefPubMedGoogle Scholar
  12. Du, D., Zhu, Y., Wei, J., Tian, Y., Niu, G., and Tan, H. (2013). Improvement of gougerotin and nikkomycin production by engineering their biosynthetic gene clusters. Appl Microbiol Biotechnol 97, 6383–6396.CrossRefPubMedGoogle Scholar
  13. Engel, P., and Ullah, A.H.J. (1988). Mutation affecting peptide bond formation in nikkomycin biosynthesis. Biochem Biophysical Res Commun 156, 695–700.CrossRefGoogle Scholar
  14. Feng, C., Ling, H., Du, D., Zhang, J., Niu, G., and Tan, H. (2014a). Novel nikkomycin analogues generated by mutasynthesis in Streptomyces ansochromogenes. Microb Cell Fact 13, 59.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Feng, J., Wu, J., Dai, N., Lin, S., Xu, H.H., Deng, Z., and He, X. (2013). Discovery and characterization of BlsE, a radical S-adenosyl-L-methionine decarboxylase involved in the blasticidin S biosynthetic pathway. PLoS ONE 8, e68545.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Feng, J., Wu, J., Gao, J., Xia, Z., Deng, Z., and He, X. (2014b). Biosynthesis of the b-methylarginine residue of peptidyl nucleoside arginomycin in Streptomyces arginensis NRRL 15941. Appl Environ Microbiol 80, 5021–5027.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ginj, C., Rüegger, H., Amrhein, N., and Macheroux, P. (2005). 3’-Enolpyruvyl-UMP, a novel and unexpected metabolite in nikkomycin biosynthesis. ChemBioChem 6, 1974–1976.CrossRefPubMedGoogle Scholar
  18. Gomez-Escribano, J.P., and Bibb, M.J. (2011). Engineering Streptomyces coelicolor for heterologous expression of secondary metabolite gene clusters. Microbial Biotech 4, 207–215.CrossRefGoogle Scholar
  19. Gould, S.J., and Guo, J. (1994). Cytosylglucuronic acid synthase (cytosine: UDP-glucuronosyltransferase) from Streptomyces griseochromogenes, the first prokaryotic UDP-glucuronosyltransferase.. J Bacteriol 176, 1282–1286.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Grochowski, L.L., and Zabriskie, T.M. (2006). Characterization of BlsM, a nucleotide hydrolase involved in cytosine production for the biosynthesis of blasticidin S. ChemBioChem 7, 957–964.CrossRefPubMedGoogle Scholar
  21. He, N., Wu, P., Lei, Y., Xu, B., Zhu, X., Xu, G., Gao, Y., Qi, J., Deng, Z., Tang, G., Chen, W., and Xiao, Y. (2017). Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics. Chem Sci 8, 444–451.CrossRefPubMedGoogle Scholar
  22. Holden, W.M., Fites, J.S., Reinert, L.K., and Rollins-Smith, L.A. (2014). Nikkomycin Z is an effective inhibitor of the chytrid fungus linked to global amphibian declines. Fungal Biol 118, 48–60.CrossRefPubMedGoogle Scholar
  23. Huang, K.T., Misato, T., and Asuyama, H. (1964a). Effect of blasticidin S on protein synthesis of Piricularia Oryzae. J Antibiot 17, 65–70.PubMedGoogle Scholar
  24. Huang, K.T., Misato, T., and Asuyama, H. (1964b). Selective toxicity of blasticidin S to Piricularia Oryzae and Pellicularia Sasakii. J Antibiot 17, 71–74.PubMedGoogle Scholar
  25. Isono, K. (1988). Nucleoside antibiotics: structure, biological activity, and biosynthesis. J Antibiot 41, 1711–1739.CrossRefPubMedGoogle Scholar
  26. Jia, L., Tian, Y., and Tan, H. (2007). SanT, a bidomain protein, is essential for nikkomycin biosynthesis of Streptomyces ansochromogenes. Biochem Biophys Res Commun 362, 1031–1036.CrossRefPubMedGoogle Scholar
  27. Komatsu, M., Uchiyama, T., Omura, S., Cane, D.E., and Ikeda, H. (2010). Genome-minimized Streptomyces host for the heterologous expression of secondary metabolism. Proc Natl Acad Sci USA 107, 2646–2651.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lauer, B., Russwurm, R., and Bormann, C. (2000). Molecular characterization of two genes from Streptomyces tendae Tü901 required for the formation of the 4-formyl-4-imidazolin-2-one-containing nucleoside moiety of the peptidyl nucleoside antibiotic nikkomycin. Eur J Biochem 267, 1698–1706.CrossRefPubMedGoogle Scholar
  29. Lauer, B., Russwurm, R., Schwarz, W., Kálmánczhelyi, A., Bruntner, C., Rosemeier, A., and Bormann, C. (2001). Molecular characterization of co-transcribed genes from Streptomyces tendae Tü901 involved in the biosynthesis of the peptidyl moiety and assembly of the peptidyl nucleoside antibiotic nikkomycin. Mol Gen Genet 264, 662–673.CrossRefPubMedGoogle Scholar
  30. Li, J., Li, L., Feng, C., Chen, Y., and Tan, H. (2012). Novel polyoxins generated by heterologously expressing polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes. Microb Cell Fact 11, 135.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Li, J., Li, L., Tian, Y., Niu, G., and Tan, H. (2011). Hybrid antibiotics with the nikkomycin nucleoside and polyoxin peptidyl moieties. Metab Eng 13, 336–344.CrossRefPubMedGoogle Scholar
  32. Li, L., Jiang, W., and Lu, Y. (2017a). New strategies and approaches for engineering biosynthetic gene clusters of microbial natural products. Biotech Adv http://dx.doi.org/10.1016/j.biotechadv.2017.03.007.Google Scholar
  33. Li, L., Xu, Z., Xu, X., Wu, J., Zhang, Y., He, X., Zabriskie, T.M., and Deng, Z. (2008). The mildiomycin biosynthesis: initial steps for sequential generation of 5-hydroxymethylcytidine 5’-monophosphate and 5-hydroxymethylcytosine in Streptoverticillium rimofaciens ZJU5119. ChemBioChem 9, 1286–1294.CrossRefPubMedGoogle Scholar
  34. Li, L., Zheng, G., Chen, J., Ge, M., Jiang, W., and Lu, Y. (2017b). Multiplexed site-specific genome engineering for overproducing bioactive secondary metabolites in actinomycetes. Metab Eng 40, 80–92.CrossRefPubMedGoogle Scholar
  35. Li, Y., Ling, H., Li, W., and Tan, H. (2005). Improvement of nikkomycin production by enhanced copy of sanU and sanV in Streptomyces ansochromogenes and characterization of a novel glutamate mutase encoded by sanU and sanV. Metab Eng 7, 165–173.CrossRefPubMedGoogle Scholar
  36. Li, Y., Zeng, H., and Tan, H. (2004). Cloning, function, and expression of sanS: a gene essential for nikkomycin biosynthesis of Streptomyces ansochromogenes. Curr Microbiol 49, 128–132.PubMedGoogle Scholar
  37. Liao, G., Li, J., Li, L., Yang, H., Tian, Y., and Tan, H. (2009). Selectively improving nikkomycin Z production by blocking the imidazolone biosynthetic pathway of nikkomycin X and uracil feeding in Streptomyces ansochromogenes. Microb Cell Fact 8, 61.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Liao, G., Li, J., Li, L., Yang, H., Tian, Y., and Tan, H. (2010). Cloning, reassembling and integration of the entire nikkomycin biosynthetic gene cluster into Streptomyces ansochromogenes lead to an improved nikkomycin production. Microb Cell Fact 9, 6.CrossRefPubMedPubMedCentralGoogle Scholar
  39. Lilla, E.A., and Yokoyama, K. (2016). Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes. Nat Chem Biol 12, 905–907.CrossRefPubMedPubMedCentralGoogle Scholar
  40. Ling, H., Wang, G., Tian, Y., Liu, G., and Tan, H. (2007). SanM catalyzes the formation of 4-pyridyl-2-oxo-4-hydroxyisovalerate in nikkomycin biosynthesis by interacting with SanN. Biochem Biophysical Res Commun 361, 196–201.CrossRefGoogle Scholar
  41. Ling, H, Wang, G, Li, J, and Tan, H. (2008). sanN encoding a dehydrogenase is essential for nikkomycin biosynthesis in Streptomyces ansochromogenes. J Microbiol Biotechnol 18, 397–403.PubMedGoogle Scholar
  42. Liu, G., Chater, K.F., Chandra, G., Niu, G., and Tan, H. (2013). Molecular regulation of antibiotic biosynthesis in Streptomyces. Microbiol Mol Biol Rev 77, 112–143.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Liu, G., Tian, Y., Yang, H., and Tan, H. (2005). A pathway-specific transcriptional regulatory gene for nikkomycin biosynthesis inStreptomyces ansochromogenes that also influences colony development. Mol Microbiol 55, 1855–1866.CrossRefPubMedGoogle Scholar
  44. Luo, Y., Enghiad, B., and Zhao, H. (2016). New tools for reconstruction and heterologous expression of natural product biosynthetic gene clusters. Nat Prod Rep 33, 174–182.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Moon, M., and Van Lanen, S.G. (2010). Characterization of a dual specificity aryl acid adenylation enzyme with dual function in nikkomycin biosynthesis. Biopolymers 93, 791–801.CrossRefPubMedGoogle Scholar
  46. Niu, G., Li, L., Wei, J., and Tan, H. (2013). Cloning, heterologous expression, and characterization of the gene cluster required for gougerotin biosynthesis. Chem Biol 20, 34–44.CrossRefPubMedGoogle Scholar
  47. Niu, G., Liu, G., Tian, Y., and Tan, H. (2006). SanJ, an ATP-dependent picolinate-CoA ligase, catalyzes the conversion of picolinate to picolinate-CoA during nikkomycin biosynthesis in Streptomyces ansochromogenes. Metab Eng 8, 183–195.CrossRefPubMedGoogle Scholar
  48. Niu, G., and Tan, H. (2015). Nucleoside antibiotics: biosynthesis, regulation, and biotechnology. Trends Microbiol 23, 110–119.CrossRefPubMedGoogle Scholar
  49. Nix, D.E., Swezey, R.R., Hector, R., and Galgiani, J.N. (2009). Pharmacokinetics of nikkomycin Z after single rising oral doses. Antimicrob Agents Chemother 53, 2517–2521.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Oberdorfer, G., Binter, A., Ginj, C., Macheroux, P., and Gruber, K. (2012). Structural and functional characterization of NikO, an enolpyruvyl transferase essential in nikkomycin biosynthesis. J Biol Chem 287, 31427–31436.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pan, Y., Liu, G., Yang, H., Tian, Y., and Tan, H. (2009). The pleiotropic regulator AdpA-L directly controls the pathway-specific activator of nikkomycin biosynthesis in Streptomyces ansochromogenes. Mol Microbiol 72, 710–723.CrossRefPubMedGoogle Scholar
  52. Preeti, M.C., Santosh, G.T., and Mukund, V.D. (2013). Chitin Synthase Inhibitors as antifungal agents. Mini Rev Med Chem 13, 222–236.Google Scholar
  53. Qi, J., Liu, J., Wan, D., Cai, Y.S., Wang, Y., Li, S., Wu, P., Feng, X., Qiu, G., Yang, S.P., Chen, W., and Deng, Z. (2015). Metabolic engineering of an industrial polyoxin producer for the targeted overproduction of designer nucleoside antibiotics. Biotechnol Bioeng 112, 1865–1871.CrossRefPubMedGoogle Scholar
  54. Qi, J., Wan, D., Ma, H., Liu, Y., Gong, R., Qu, X., Sun, Y., Deng, Z., and Chen, W. (2016). Deciphering carbamoylpolyoxamic acid biosynthesis reveals unusual acetylation cycle associated with tandem reduction and sequential hydroxylation. Cell Chem Biol 23, 935–944.CrossRefPubMedGoogle Scholar
  55. Rutledge, P.J., and Challis, G.L. (2015). Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat Rev Micro 13, 509–523.CrossRefGoogle Scholar
  56. Shubitz, L.F., Roy, M.E., Nix, D.E., and Galgiani, J.N. (2013). Efficacy of nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs. Med Mycol 51, 747–754.CrossRefPubMedGoogle Scholar
  57. Stenland, C.J., Lis, L.G., Schendel, F.J., Hahn, N.J., Smart, M.A., Miller, A.L., von Keitz, M.G., and Gurvich, V.J. (2013). A practical and scalable manufacturing process for an anti-fungal agent, nikkomycin Z. Org Process Res Dev 17, 265–272.CrossRefPubMedPubMedCentralGoogle Scholar
  58. Venci, D., Zhao, G., and Jorns, M.S. (2002). Molecular characterization of NikD, a new flavoenzyme important in the biosynthesis of nikkomycin antibiotics. Biochemistry 41, 15795–15802.CrossRefPubMedGoogle Scholar
  59. Wang, G., Nie, L., and Tan, H. (2003). Cloning and characterization of sanO, a gene involved in nikkomycin biosynthesis in Streptomyces ansochromogenes. Lett Appl Microbiol 37, 452–457.CrossRefPubMedGoogle Scholar
  60. Wang, G., and Tan, H. (2004). Enhanced production of nikkomycin X by over-expression of SanO, a non-ribosomal peptide synthetase in Streptomyces ansochromogenes. Biotech Lett 26, 229–233.CrossRefGoogle Scholar
  61. Weber, T., Charusanti, P., Musiol-Kroll, E.M., Jiang, X., Tong, Y., Kim, H.U., and Lee, S.Y. (2015). Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes. Trends Biotech 33, 15–26.CrossRefGoogle Scholar
  62. Winn, M., Goss, R.J.M., Kimura, K., and Bugg, T.D.H. (2010). Antimicrobial nucleoside antibiotics targeting cell wall assembly: recent advances in structure-function studies and nucleoside biosynthesis. Nat Prod Rep 27, 279–304.CrossRefPubMedGoogle Scholar
  63. Wu, J., Li, L., Deng, Z., Zabriskie, T.M., and He, X. (2012). Analysis of the mildiomycin biosynthesis gene cluster in Streptoverticillum remofaciens ZJU5119 and characterization of MilC, a hydroxymethyl cytosyl-glucuronic acid synthase. ChemBioChem 13, 1613–1621.CrossRefPubMedGoogle Scholar
  64. Xie, Z., Niu, G., Li, R., Liu, G., and Tan, H. (2007). Identification and characterization of sanH and sanI involved in the hydroxylation of pyridyl residue during nikkomycin biosynthesis in Streptomyces ansochromogenes. Curr Microbiol 55, 537–542.CrossRefPubMedGoogle Scholar
  65. Yu, G., Li, L., Liu, X., Liu, G., Deng, Z., Zabriskie, M.T., Jiang, M., and He, X. (2015). The standalone aminopeptidase PepN catalyzes the maturation of blasticidin S from leucylblasticidin S. Sci Rep 5, 17641.CrossRefPubMedPubMedCentralGoogle Scholar
  66. Zeng, H., Tan, H., and Li, J. (2002). Cloning and function of sanQ: a gene involved in nikkomycin biosynthesis of Streptomyces ansochromogenes. Curr Microbiol 45, 175–179.CrossRefPubMedGoogle Scholar
  67. Zhai, L., Lin, S., Qu, D., Hong, X., Bai, L., Chen, W., and Deng, Z. (2012). Engineering of an industrial polyoxin producer for the rational production of hybrid peptidyl nucleoside antibiotics. Metabolic Eng 14, 388–393.CrossRefGoogle Scholar
  68. Zhang, G., Zhang, H., Li, S., Xiao, J., Zhang, G., Zhu, Y., Niu, S., Ju, J., and Zhang, C. (2012). Characterization of the amicetin biosynthesis gene cluster from Streptomyces vinaceusdrappus NRRL 2363 implicates two alternative strategies for amide bond formation. Appl Environ Microbiol 78, 2393–2401.CrossRefPubMedPubMedCentralGoogle Scholar
  69. Zhao, G., Chen, C., Xiong, W., Gao, T., Deng, Z., Wu, G., and He, X. (2016). Structural basis of the substrate preference towards CMP for a thymidylate synthase MilA involved in mildiomycin biosynthesis. Sci Rep 6, 39675.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Zhao, G., Wu, G., Zhang, Y., Liu, G., Han, T., Deng, Z., and He, X. (2014). Structure of theN-glycosidase MilB in complex with hydroxymethyl CMP reveals its Arg23 specifically recognizes the substrate and controls its entry. Nucleic Acids Res 42, 8115–8124.CrossRefPubMedPubMedCentralGoogle Scholar

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© Science China Press and Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.State Key Laboratory of Microbial Resources, Institute of MicrobiologyChinese Academy of SciencesBeijingChina
  2. 2.Biotechnology Research CenterSouthwest UniversityChongqingChina
  3. 3.University of Chinese Academy of SciencesBeijingChina

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