Systematics-guided bioprospecting for bioactive microbial natural products

Abstract

Advances in the taxonomic characterization of microorganisms have accelerated the rate at which new producers of natural products can be understood in relation to known organisms. Yet for many reasons, chemical efforts to characterize new compounds from new microbes have not kept pace with taxonomic advances. That there exists an ever-widening gap between the biological versus chemical characterization of new microorganisms creates tremendous opportunity for the discovery of novel natural products through the calculated selection and study of organisms from unique, untapped, ecological niches. A systematics-guided bioprospecting, including the construction of high quality libraries of marine microbes and their crude extracts, investigation of bioactive compounds, and increasing the active compounds by precision engineering, has become an efficient approach to drive drug leads discovery. This review outlines the recent advances in these issues and shares our experiences on anti-infectious drug discovery and improvement of avermectins production as well.

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References

  1. Afeltra J, Verweij PE (2003) Antifungal activity of nonantifungal drugs. Eur J Clin Microbiol Infect Dis 22:397–407

    PubMed  Article  CAS  Google Scholar 

  2. Ashforth EJ, Fu C, Liu X, Dai H, Song F, Guo H, Zhang L (2010) Bioprospecting for antituberculosis leads from microbial metabolites. Nat Prod Rep 27:1709–1719

    PubMed  Article  CAS  Google Scholar 

  3. Askenazi M, Driggers EM, Holtzman DA, Norman TC, Iverson S, Zimmer DP, Boers ME, Blomquist PR, Martinez EJ, Monreal AW, Feibelman TP, Mayorga ME, Maxon ME, Sykes K, Tobin JV, Cordero E, Salama SR, Trueheart J, Royer JC, Madden KT (2003) Integrating transcriptional and metabolite profiles to direct the engineering of lovastatin-producing fungal strains. Nat Biotechnol 21:150–156

    PubMed  Article  CAS  Google Scholar 

  4. Baltz RH (2007) Antimicrobials from actinomycetes: back to the future. Microbe 2:125–131

    Google Scholar 

  5. Berdy J (2005) Bioactive microbial metabolites. J Antibiot 58:1–26

    PubMed  Article  CAS  Google Scholar 

  6. Bian J, Li Y, Wang J, Song FH, Liu M, Dai HQ, Ren B, Gao H, Hu X, Liu ZH, Li WJ, Zhang L (2009) Amycolatopsis marina sp. nov., an actinomycete isolated from an ocean sediment. Int J Syst Evol Microbiol 59:477–481

    Google Scholar 

  7. Bian J et al (2010) Amycolatopsis marina sp. nov., an actinomycete isolated from an ocean sediment. Int J Syst Evol Microbiol 59:477–481

    Article  Google Scholar 

  8. Bobzin SC, Yang S, Kasten TP (2000) LC–NMR: a new tool to expedite the dereplication and identification of natural products. J Ind Microbiol Biotechnol 25:342–345

    PubMed  Article  CAS  Google Scholar 

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

    PubMed  Article  CAS  Google Scholar 

  10. Borresen T, Boyen C, Dobson A, Höfle M, Ianora A, Jaspars M, Kijjoa A, Olafsen J, Rigos G, Wijffels RH (2010) Marine biotechnology: a new vision and strategy for Europe. Marine Board—ESF Position Paper 15, pp 1–93

  11. Bull AT, Stach JEM (2007) Marine actinobacteria: new opportunities for natural product search and discovery. Trends Microbiol 15:491–499

    PubMed  Article  CAS  Google Scholar 

  12. Bull AT, Goodfellow M, Slater JH (1992) Biodiversity as a source of innovation in biotechnology. Annu Rev Microbiol 46:219–252

    PubMed  Article  CAS  Google Scholar 

  13. Burg RW, Miller BM, Baker EE, Birnbaum J, Currie SA, Hartman R, Kong YL, Monaghan RL, Olson G, Putter I, Tunac JB, Wallick H, Stapley EO, Oiwa R, Omura S (1979) Avermectins, new family of potent anthelmintic agents: producing organism and fermentation. Antimicrob Agents Chemother 15:361–367

    PubMed  CAS  Google Scholar 

  14. Cao Y, Jiang Y, Hua XL (2009) Great Shangri-La composition analysis of soil actinomycetes and biological activity determination. Acta Microbiol Sin 49:105–109

    CAS  Google Scholar 

  15. Carvalho AL, Cardoso FS, Bohn A, Neves AR, Santos H (2011) Engineering trehalose synthesis in Lactococcus lactis for improved stress tolerance. Appl Environ Microbiol 77:4189–4199

    PubMed  Article  CAS  Google Scholar 

  16. Changsen C, Franzblau SG, Palittapongarnpim P (2003) Improved green fluorescent protein reporter gene-based microplate screening for antituberculosis compounds by utilizing an acetamidase promoter. Antimicrob Agents Chemother 47:3682–3687

    PubMed  Article  CAS  Google Scholar 

  17. Corcoran O, Spraul M (2003) LC–NMR–MS in drug discovery. Drug Discov Today 8:624–631

    PubMed  Article  CAS  Google Scholar 

  18. Dai HQ, Wang J, Xin YH, Pei G, Tang SK, Ren B, Ward A, Ruan JS, Li WJ, Zhang LX (2009) Verrucosispora sediminis sp. nov., a novel cyclodipeptide-producing actinomycete from the South China Sea. Int J Syst Evol Microbiol 60:1807–1812

    PubMed  Article  Google Scholar 

  19. Demain AL, Sanchez S (2009) Microbial drug discovery: 80 years of progress. J Antibiot 62:5–16

    PubMed  Article  CAS  Google Scholar 

  20. Dhiman RK, Schaeffer ML, Bailey AM, Testa CA, Scherman H, Crick DC (2005) 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (Ispc) from Mycobacterium tuberculosis: towards understanding mycobacterial resistance to fosmidomycin. J Bacteriol 187:8395–8402

    PubMed  Article  CAS  Google Scholar 

  21. Elander RP (2003) Industrial production of beta-lactam antibiotics. Appl Microbiol Biotechnol 61:385–392

    PubMed  CAS  Google Scholar 

  22. Farnet CM, Zazopoulos E (2005) Improving drug discovery from microorganisms. In: Zhang L, Demain AL (eds) Natural products: drug discovery and therapeutics. Humana Press, New York, pp 95–106

    Google Scholar 

  23. Fukuda T, Arai M, Yamaguchi Y, Masuma R, Tomoda H, Omura S (2004) New beauvericins, potentiators of antifungal miconazole activity, produced by Beauveria sp. FK1-1366. Taxonomy, fermentation, isolation and biological properties. J Antibiot 57:110–116

    PubMed  CAS  Google Scholar 

  24. Fukuda T, Hasegawa Y, Hagimori K, Yamaguchi Y, Masuma R, Tomoda H, Omura S (2006) Tensidols, new potentiators of antifungal miconazole activity, produced by Aspergillus niger FKI-2342J. J Antibiot 59:480–485

    PubMed  Article  CAS  Google Scholar 

  25. Galm U, Shen B (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  Google Scholar 

  26. Gao H, Zhou XZ, Gou Z, Zhuo Y, Fu C, Liu M, Song F, Ashforth E, Zhang L (2010a) Rational design for over-production of desirable microbial metabolites by precision engineering. Antonie Leeuwenhoek 98:151–163

    PubMed  Article  Google Scholar 

  27. Gao H, Liu M, Zhou X, Liu J, Zhuo Y, Gou Z, Xu B, Zhang W, Liu X, Luo A, Zheng C, Chen X, Zhang L (2010b) Identification of avermectin-high-producing strains by high-throughput screening methods. Appl Microbiol Biotechnol 85:1219–1225

    PubMed  Article  CAS  Google Scholar 

  28. Gu JQ, Wang YH, Franzblau SG, Montenegro G, Timmermann BN (2006) Dereplication of pentacyclic triterpenoids in plants by GC-EI/MS. Phytochem Anal 17:102–106

    PubMed  Article  CAS  Google Scholar 

  29. Heitman J (2005) A fungal achilles’ heel. Science 309:2175–2176

    PubMed  Article  CAS  Google Scholar 

  30. Hermann T (2003) Industrial production of amino acids by coryneform bacteria. J Biotechnol 104:155–172

    PubMed  Article  CAS  Google Scholar 

  31. Ikeda H, Omura S (1995) Control of avermectin biosynthesis in Streptomyces avermitilis for the selective production of a useful component. J Antibiot (Tokyo) 48:549–562

    CAS  Google Scholar 

  32. Jensen PR, Fenical W (1996) Marine bacterial diversity as a resource for novel microbial products. J Ind Microbiol Biotechnol 17:346–351

    Article  CAS  Google Scholar 

  33. Knight V, Sanglier JJ, DiTullio D, Braccili S, Bonner P, Waters J, Hughes D, Zhang L (2003) Diversifying microbial natural products for drug discovery. Appl Microbiol Biotechnol 62:446–458

    PubMed  Article  CAS  Google Scholar 

  34. Konishi Y, Kiyota T, Draghici C, Gao JM, Yeboah F, Acoca S, Jarussophon S, Purisima E (2007) Molecular formula analysis by an MS/MS/MS technique to expedite dereplication of natural products. Anal Chem 79:1187–1197

    PubMed  Article  CAS  Google Scholar 

  35. Lambert M, Staerk D, Hansen SH, Sairafianpour M, Jaroszewski JW (2005) Rapid extract dereplication using HPLC-SPE-NMR: analysis of isoflavonoids from Smirnowia iranica. J Nat Prod 68:1500–1509

    PubMed  Article  CAS  Google Scholar 

  36. Lang G, Mayhudin NA, Mitova MI, Sun L, van der Sar S, Blunt JW, Cole AL, Ellis G, Laatsch H, Munro MH (2008) Evolving trends in the dereplication of natural product extracts: new methodology for rapid, small-scale investigation of natural product extracts. J Nat Prod 71:1595–1599

    PubMed  Article  CAS  Google Scholar 

  37. Larsen TO, Smedsgaard J, Nielsen KF, Hansen ME, Frisvad JC (2005) Phenotypic taxonomy and metabolite profiling in microbial drug discovery. Nat Prod Rep 22:672–695

    PubMed  Article  CAS  Google Scholar 

  38. Leonard E, Ajikumara PK, Thayerb K, Xiao WH, Moa JD, Tidorb B, Stephanopoulosa G, Prathera KLJ (2010) Combining metabolic and protein engineering of a terpenoid biosynthetic pathway for overproduction and selectivity control. Proc Natl Acad Sci USA 107:13654–13659

    PubMed  Article  CAS  Google Scholar 

  39. Liu X, Ashforth E, Ren B, Song F, Dai H, Liu M, Wang J, Xie Q, Zhang L (2010) Bioprospecting microbial natural product libraries from the marine environment for drug discovery. J Antibiot 63:415–422

    PubMed  Article  CAS  Google Scholar 

  40. Llacer E, Urpi Fl, Vilarrasa J (2009) Efficient approach to fluvirucins B2-B5, Sch 38518, and Sch 39185. First synthesis of their aglycon, via CM and RCM reactions. Org Lett 11:3198–3201

    PubMed  Article  CAS  Google Scholar 

  41. Mao J, Wang J, Dai HQ, Zhang ZD, Tang QY, Ren B, Yang N, Goodfellow M, Zhang LX, Liu ZH (2010) Yuhushiella Deserti gen. nov., sp. nov., a new genus of the suborder Pseudonocardineae. Int J Syst Evol Microbiol 61:621–630

    PubMed  Article  Google Scholar 

  42. Mishra KP, Ganju L, Sairam M, Banerjee PK, Sawhney RC (2008) A review of high throughput technology for the screening of natural products. Biomed Pharmacother 62:94–98

    PubMed  Article  CAS  Google Scholar 

  43. Moon TS, Yoon SH, Lanza AM, Roy-Mayhew JD, Prather KJ (2009) Production of glucaric acid from a synthetic pathway in recombinant Escherichia coli. Appl Environ Microbiol 75:589–595

    PubMed  Article  CAS  Google Scholar 

  44. Mueller UG, Sen R (2009) A re-evaluation of the symbiosis between fungus-growing ants and actinomycetes bacteria. 15th International symposium on the biology of actinomycetes, Shanghai, China, p 6

  45. Ostergaard S, Roca C, Rønnow B, Nielsen J, Olsson L (2000) Physiological studies in aerobic batch cultivations of Saccharomyces cerevisiae strains harboring the MEL1 gene. Biotechnol Bioeng 68:252–259

    PubMed  Article  CAS  Google Scholar 

  46. Patnaik R (2008) Engineering complex phenotypes in industrial strains. Biotechnol Prog 24:38–47

    PubMed  Article  CAS  Google Scholar 

  47. Pauli GF, Case RJ, Inui T, Wang Y, Cho S, Fischer NH, Franzblau SG (2005) New perspectives on natural products in TB drug research. Life Sci 78:485–494

    PubMed  Article  CAS  Google Scholar 

  48. Runquist D, Hägerdal BH, Bettiga M (2010) Increased ethanol productivity in xylose-utilizing Saccharomyces cerevisiae via a randomly mutagenized xylose reductase. Appl Environ Microbiol 76:7796–7802

    PubMed  Article  CAS  Google Scholar 

  49. Russell DJ, Hadden CE, Martin GE, Gibson AA, Zens AP, Carolan JLA (2000) Comparison of inverse-detected heteronuclear NMR performance: conventional vs cryogenic microprobe performance. J Nat Prod 63:1047–1049

    PubMed  Article  CAS  Google Scholar 

  50. Sanda T, Hasunuma T, Matsuda F, Kondo A (2011) Repeated-batch fermentation of lignocellulosic hydrolysate to ethanol using a hybrid Saccharomyces cerevisiae strain metabolically engineered for tolerance to acetic and formic acids. Bioresour Technol. doi:10.1016/j.biortech.2011.06.028

  51. Shawar RM, Humble DJ, Van Dalfsen JM, Stover CK, Hickey MJ, Steele S, Mitscher LA, Baker W (1997) Rapid screening of natural products for anti-mycobacterial activity by using luciferase-expressing strains of Mycobacterium bovis BCG and Mycobacterium intracellulare. Antimicrob Agents Chemother 41:570–574

    PubMed  CAS  Google Scholar 

  52. Sichwart S, Hetzler S, Bröker D, Steinbüchel A (2011) Extension of the substrate utilization range of Ralstonia eutropha H16 by metabolic engineering to include mannose and glucose. Appl Environ Microbiol 77:1325–1334

    PubMed  Article  CAS  Google Scholar 

  53. Singh SB, Zink DL, Dorso K, Motyl M, Salazar O, Basilio A, Vicente F, Byrne KM, Ha S, Genilloud O (2009) Isolation, structure, and antibacterial activities of Lucensimycins DG, discovered from Streptomyces lucensis MA7349 using an antisense strategy. J Nat Prod 72:345–352

    PubMed  Article  CAS  Google Scholar 

  54. Song F, Dai H, Tong Y, Ren B, Chen C, Sun N, Liu X, Bian J, Liu M, Gao H, Liu H, Chen X, Zhang L (2010) Trichoderma ketones A–D and 7-O-methylkoninginin D from the marine fungus. Trichoderma koningii. J Nat Prod 73:806–810

    PubMed  Article  CAS  Google Scholar 

  55. Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K (2000) Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 50-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci USA 97:1433–1437

    PubMed  Article  CAS  Google Scholar 

  56. Stierle AA, Stierle DB, Kemp K (2004) Novel sesquiterpenoids with matrix metalloproteinase-3 inhibitory activity from an acid mine waste extremophile. J Nat Prod 67:1392–1395

    PubMed  Article  CAS  Google Scholar 

  57. Stierle AA, Stierle DB, Kelly K (2006) Berkelic acid, a novel spiroketal with selective anticancer activity from an acid mine waste fungal extremophile. J Org Chem 71:5357–5360

    PubMed  Article  CAS  Google Scholar 

  58. Tang QY, Yang N, Wang J, Xie YQ, Ren B, Zhou YG, Gu MY, Mao J, Li WJ, Shi YH, Zhang LX (2011). Paenibacillus algorifonticola sp. nov., isolated from a cold spring in China. Int J Syst Evol Microbiol 61:2167–2172

  59. Tormo JR, García JB, DeAntonio M, Feliz J, Mira A, Díez MT, Hernández P, Peláez F (2003) A method for the selection of production media for actinomycete strains based on their metabolite HPLC profiles. J Ind Microbiol Biotechnol 30:582–588

    Article  CAS  Google Scholar 

  60. Wagner M, Gierth A, Abdel-Mageed W, Jaspers M, Goodfellow M, Bull AT, Horikoshi K, Fiedler HP (2009) Dermacozines: drugs from the abyss, 15th international symposium on the biology of actinomycetes, Shanghai, China, 20–25 August, p 43

  61. Wang J, Soisson SM, Young K, Shoop W, Kodali S, Galgoci A, Painter R, Parthasarathy G, Tnag YS, Cummings R, Ha S, Dorso K, Motyl M, Jayasuriya H, Ondeyka J, Herath K, Zhang C, Hernandez L, Allocco J, Basilio A, Tormo JR, Genilloud O, Vicente F, Pelaez F, Colwell L, Lee SH, Michael B, Felcetto T, Gill C, Silver LL, Hermes JD, Bartizal K, Barrett J, Schmatz D, Becker JW, Cully D, Singh SB (2006) Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441:358–361

    PubMed  Article  CAS  Google Scholar 

  62. Wang J, Kodali S, Lee SH, Galgoci A, Painter R, Dorso K, Racine F, Motyl M, Hernandez L, Tinney E, Colletti SL, Herath K, Cummings R, Salazar O, González I, Basilio A, Vicente F, Genilloud O, Pelaez F, Jayasuriya H, Young K, Cully DF, Singh SB (2007) Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc Natl Acad Sci USA 104:7612–7616

    PubMed  Article  CAS  Google Scholar 

  63. Wang J, Li Y, Bian J, Tang SK, Ren B, Chen M, Li WJ, Zhang LX (2009) Prauserella marina sp. nov., isolated from ocean sediment of the South China Sea. Int J Syst Evol Microbiol 60:985–989

    PubMed  Article  Google Scholar 

  64. Wolfender JL, Waridel P, Ndjoko K, Hobby KR, Major HJ, Hostettmann K (2000) Evaluation of Q-TOF-MS/MS and multiple stage IT-MSn for the dereplication of flavonoids and related compounds in crude plant extracts. Analysis 28:895–906

    Article  CAS  Google Scholar 

  65. Xu Z, Zhang LX, Zhang JD, Cao YB, Yu YY, Wang DJ, Ying K, Chen WS, Jiang YY (2006) cDNA microarray analysis of differential gene expression and regulation in clinically drug-resistant isolates of Candida albicans from bone marrow transplanted patients. Int J Med Microbiol 296:421–434

    PubMed  Article  CAS  Google Scholar 

  66. You J, Dai H, Chen Z, Liu G, He Z, Song F, Yang X, Fu H, Zhang L, Chen X (2010) Trichoderone, a novel cytotoxic cyclopentenone and cholesta-7, 22-diene-3 beta, 5 alpha, 6 beta-triol, with new activities from the marine-derived fungus Trichoderma sp. J Ind Microbiol Biotechnol 37:245–252

    PubMed  Article  CAS  Google Scholar 

  67. Yuan T, Yin C, Zhu C, Zhu B, Hu Y (2011) Improvement of antibiotic productivity by knock-out of dauW in Streptomyces coeruleobidus. Microbiol Res. doi:10.1016/j.micres.2010.10.006

  68. Zazopoulos E, Huang K, Staffa A, Liu W, Bachmann BO, Nonaka K et al (2003) A genomics guided approach for discovering and expressing cryptic metabolic pathways. Nat Biotechnol 21:187–190

    PubMed  Article  CAS  Google Scholar 

  69. Zhang L, An R, Wang J, Sun N, Zhang S, Hu J, Kuai J (2005) Exploring novel bioactive compounds from marine microbes. Curr Opin Microbiol 8:276–281

    PubMed  Article  CAS  Google Scholar 

  70. Zhang L, Yan K, Zhang Y, Huang R, Bian J, Zheng C, Sun H, Chen Z, Sun N, An R, Min F, Zhao W, Zhuo Y, You J, Song Y, Yu Z, Liu Z, Yang K, Gao H, Dai H, Zhang X, Wang J, Fu C, Pei G, Liu J, Zhang S, Goodfellow M, Jiang Y, Kuai J, Zhou G, Chen X (2007) High-throughput synergy screening identifies microbial metabolites as combination agents for the treatment of fungal infections. Proc Natl Acad Sci USA 104:4606–4611

    PubMed  Article  CAS  Google Scholar 

  71. Zhang C, Occi J, Masurekar P, Barrett JF, Zink DL, Smith S, Onishi R, Ha S, Salazar O, Genilloud O, Basilio A, Vicente F, Gill C, Hichey EJ, Dorso K, Motyl M, Singh SB (2008) Isolation, structure, and antibacterial activity of philipimycin, a thiazolyl peptide discovered from Actinoplanes philippinensis MA7347. J Am Chem Soc 130:12102–12110

    PubMed  Article  CAS  Google Scholar 

  72. Zhang C, Ondeyka JG, Zink DL, Basilio A, Vicente F, Salazar O, Genilloud O, Dorso K, Motyl M, Byrne K, Gingh SB (2009) Discovery of okilactomycin and congeners from Streptomyces scabrisporus by antisense differential sensitivity assay targeting ribosomal protein S4. J Antibiot 62:55–61

    PubMed  Article  CAS  Google Scholar 

  73. Zhu T, Li J, Li L, Ma H, Che Q, Gu Q (2009) Isolation and bioactive metabolites research of Antarctic actinomycetes. 15th International symposium on the biology of actinomycetes, Shanghai, China, 20–25 August, p 56

  74. Zhuo Y, Zhang W, Chen D, Gao H, Tao J, Liu M, Gou Z, Zhou X, Ye BC, Zhang Q, Zhang S, Zhang LX (2010) Reverse biological engineering of hrdB to enhance the production of avermectins in an industrial strain of Streptomyces avermitilis. Proc Natl Acad Sci USA 107:11250–11254

    PubMed  Article  CAS  Google Scholar 

  75. Zimmermann HF, John GT, Trauthwein H, Dingerdissen U, Huthmacher K (2003) Rapid evaluation of oxygen and water permeation through microplate sealing tapes. Biotechnol Prog 19:1061–1063

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

This work was supported in part by grants from the National Natural Science Foundation of China (30901849, 30700015, 81102356, 81102369), MOST Key International Project 2007DFB31620 and 863 Hi-Tech Research and Development Program of China (2007AA09Z443), and Chinese Academy of Sciences Innovation Project (KSCXZ-YW-G-013, KSCX2-YW-R-164). This work was also supported in part by the National Science and Technology Pillar Program (no. 200703295000-02) and Important National Science and Technology Specific Projects (no. 2008ZX09401-005).

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Correspondence to Lixin Zhang.

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Xueting Liu and Krishna Bolla have contributed equally to this paper.

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Liu, X., Bolla, K., Ashforth, E.J. et al. Systematics-guided bioprospecting for bioactive microbial natural products. Antonie van Leeuwenhoek 101, 55–66 (2012). https://doi.org/10.1007/s10482-011-9671-1

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Keywords

  • Microbial natural products library
  • High-throughput screening
  • Precision engineering