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New antibiotics from bacterial natural products

Abstract

For the past five decades, the need for new antibiotics has been met largely by semisynthetic tailoring of natural product scaffolds discovered in the middle of the 20th century. More recently, however, advances in technology have sparked a resurgence in the discovery of natural product antibiotics from bacterial sources. In particular, efforts have refocused on finding new antibiotics from old sources (for example, streptomycetes) and new sources (for example, other actinomycetes, cyanobacteria and uncultured bacteria). This has resulted in several newly discovered antibiotics with unique scaffolds and/or novel mechanisms of action, with the potential to form a basis for new antibiotic classes addressing bacterial targets that are currently underexploited.

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Figure 6: The lantibiotic nisin.
Figure 7: Structures of aryl-bridged, N-acylated hexapeptides from Streptomyces natural product extracts.

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References

  1. Walsh, C.T. Antibiotics: Actions, Origins, Resistance (ASM Press, Washington; 2003).

    Google Scholar 

  2. Raju, T.N. The Nobel chronicles. 1988: James Whyte Black, (b 1924), Gertrude Elion (1918–99), and George H Hitchings (1905–98). Lancet 355, 1022 (2000).

    CAS  PubMed  Google Scholar 

  3. von Nussbaum, F., Brands, M., Hinzen, B., Weigand, S. & Habich, D. Antibacterial natural products in medicinal chemistry-exodus or revival? Angew. Chem. Int. Edn Engl. 45, 5072–5129 (2006).

    CAS  Google Scholar 

  4. Watve, M.G., Tickoo, R., Jog, M.M. & Bhole, B.D. How many antibiotics are produced by the genus Streptomyces? Arch. Microbiol. 176, 386–390 (2001).

    CAS  PubMed  Google Scholar 

  5. Baltz, R.H. Antibiotic discovery from actinomycetes: will a renaissance follow the decline and fall? SIM News 55, 186–196 (2005).

    Google Scholar 

  6. Baltz, R.H. Marcel Faber Roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration? J. Ind. Microbiol. Biotechnol. 33, 507–513 (2006).

    CAS  PubMed  Google Scholar 

  7. Arai, T. Actinomycetes: The Boundary Microorganisms (Toppan Company Limited, Tokyo, 1976).

    Google Scholar 

  8. Magarvey, N.A., Keller, J.M., Bernan, V., Dworkin, M. & Sherman, D.H. Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites. Appl. Environ. Microbiol. 70, 7520–7529 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Busti, E. et al. Antibiotic-producing ability by representatives of a newly discovered lineage of actinomycetes. Microbiology 152, 675–683 (2006).

    CAS  PubMed  Google Scholar 

  10. Amann, R.I., Ludwig, W. & Schleifer, K.H. Phylogenetic identification and in situ detection of individual microbial cells without cultivation. Microbiol. Rev. 59, 143–169 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Torsvik, V., Goksoyr, J. & Daae, F.L. High diversity in DNA of soil bacteria. Appl. Environ. Microbiol. 56, 782–787 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hugenholtz, P., Goebel, B.M. & Pace, N.R. Impact of culture-independent studies on the emerging phylogenetic view of bacterial diversity. J. Bacteriol. 180, 4765–4774 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Pace, N.R. A molecular view of microbial diversity and the biosphere. Science 276, 734–740 (1997).

    CAS  PubMed  Google Scholar 

  14. Kaeberlein, T., Lewis, K. & Epstein, S.S. Isolating “uncultivable” microorganisms in pure culture in a simulated natural environment. Science 296, 1127–1129 (2002).

    CAS  PubMed  Google Scholar 

  15. Joseph, S.J., Hugenholtz, P., Sangwan, P., Osborne, C.A. & Janssen, P.H. Laboratory cultivation of widespread and previously uncultured soil bacteria. Appl. Environ. Microbiol. 69, 7210–7215 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  18. Van Lanen, S.G. & Shen, B. Microbial genomics for the improvement of natural product discovery. Curr. Opin. Microbiol. 9, 252–260 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Walsh, C.T. Combinatorial biosynthesis of antibiotics: challenges and opportunities. ChemBioChem 3, 125–134 (2002).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Beer, S.V. & Rundle, J.R. Suppression of Erwinia amylovora by Erwinia herbicola in immature pear fruits. Phytopathology 73, 1346 (1983).

    Google Scholar 

  23. Wright, S.A., Zumoff, C.H., Schneider, L. & Beer, S.V. Pantoea agglomerans strain EH318 produces two antibiotics that inhibit Erwinia amylovora in vitro. Appl. Environ. Microbiol. 67, 284–292 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Brady, S.F. et al. Pantocin B, an antibiotic from Erwinia herbicola discovered by heterologous expression of cloned genes. J. Am. Chem. Soc. 121, 11912–11913 (1999).

    CAS  Google Scholar 

  25. Jin, M., Liu, L., Wright, S.A., Beer, S.V. & Clardy, J. Structural and functional analysis of pantocin A: an antibiotic from Pantoea agglomerans discovered by heterologous expression of cloned genes. Angew. Chem. Int. Edn Engl. 42, 2898–2901 (2003).

    CAS  Google Scholar 

  26. Jin, M., Wright, S.A., Beer, S.V. & Clardy, J. The biosynthetic gene cluster of Pantocin a provides insights into biosynthesis and a tool for screening. Angew. Chem. Int. Edn Engl. 42, 2902–2905 (2003).

    CAS  Google Scholar 

  27. Fischbach, M.A. & Walsh, C.T. Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem. Rev. 106, 3468–3496 (2006).

    CAS  PubMed  Google Scholar 

  28. Jin, M., Fischbach, M.A. & Clardy, J. A Biosynthetic gene cluster for the acetyl-CoA carboxylase inhibitor andrimid. J. Am. Chem. Soc. 128, 10660–10661 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Daniel, R. The soil metagenome–a rich resource for the discovery of novel natural products. Curr. Opin. Biotechnol. 15, 199–204 (2004).

    CAS  PubMed  Google Scholar 

  30. Rondon, M.R. et al. Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms. Appl. Environ. Microbiol. 66, 2541–2547 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang, G.Y.S. et al. Novel natural products from soil DNA libraries in a Streptomycete host. Org. Lett. 2, 2401–2404 (2000).

    CAS  PubMed  Google Scholar 

  32. Brady, S. & Clardy, J. Long-chain N-acyl amino acid antibiotics isolated from heterologously expressed environmental DNA. J. Am. Chem. Soc. 122, 12903–12904 (2000).

    CAS  Google Scholar 

  33. Brady, S.F., Chao, C.J. & Clardy, J. Long-chain N-acyltyrosine synthases from environmental DNA. Appl. Environ. Microbiol. 70, 6865–6870 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Bassler, B.L. & Losick, R. Bacterially speaking. Cell 125, 237–246 (2006).

    CAS  PubMed  Google Scholar 

  35. Brady, S.F. & Clardy, J. Palmitoylputrescine, an antibiotic isolated from the heterologous expression of DNA extracted from bromeliad tank water. J. Nat. Prod. 67, 1283–1286 (2004).

    CAS  PubMed  Google Scholar 

  36. Brady, S.F. & Clardy, J. Cloning and heterologous expression of isocyanide biosynthetic genes from environmental DNA. Angew. Chem. Int. Edn Engl. 44, 7063–7065 (2005).

    CAS  Google Scholar 

  37. Brady, S.F. & Clardy, J. Systematic investigation of the Escherichia coli metabolome for the biosynthetic origin of an isocyanide carbon atom. Angew. Chem. Int. Edn Engl. 44, 7045–7048 (2005).

    CAS  Google Scholar 

  38. MacNeil, I.A. et al. Expression and isolation of antimicrobial small molecules from soil DNA libraries. J. Mol. Microbiol. Biotechnol. 3, 301–308 (2001).

    CAS  PubMed  Google Scholar 

  39. Courtois, S. et al. Recombinant environmental libraries provide access to microbial diversity for drug discovery from natural products. Appl. Environ. Microbiol. 69, 49–55 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gillespie, D.E. et al. Isolation of antibiotics turbomycin a and B from a metagenomic library of soil microbial DNA. Appl. Environ. Microbiol. 68, 4301–4306 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bode, H.B. & Muller, R. The impact of bacterial genomics on natural product research. Angew. Chem. Int. Edn Engl. 44, 6828–6846 (2005).

    CAS  Google Scholar 

  42. Menzella, H.G. et al. Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes. Nat. Biotechnol. 23, 1171–1176 (2005).

    CAS  PubMed  Google Scholar 

  43. Menzella, H.G. et al. Redesign, synthesis and functional expression of the 6-deoxyerythronolide B polyketide synthase gene cluster. J. Ind. Microbiol. Biotechnol. 33, 22–28 (2006).

    CAS  PubMed  Google Scholar 

  44. Gullo, V.P., McAlpine, J., Lam, K.S., Baker, D. & Petersen, F. Drug discovery from natural products. J. Ind. Microbiol. Biotechnol. 33, 523–531 (2006).

    CAS  PubMed  Google Scholar 

  45. McAlpine, J.B. et al. Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent, as an example. J. Nat. Prod. 68, 493–496 (2005).

    CAS  PubMed  Google Scholar 

  46. Krab, I.M. & Parmeggiani, A. Mechanisms of EF-Tu, a pioneer GTPase. Prog. Nucleic Acid Res. Mol. Biol. 71, 513–551 (2002).

    CAS  PubMed  Google Scholar 

  47. Parmeggiani, A. et al. Structural basis of the action of pulvomycin and GE2270 A on elongation factor Tu. Biochemistry 45, 6846–6857 (2006).

    CAS  PubMed  Google Scholar 

  48. Parmeggiani, A. et al. Enacyloxin IIa pinpoints a binding pocket of elongation factor Tu for development of novel antibiotics. J. Biol. Chem. 281, 2893–2900 (2006).

    CAS  PubMed  Google Scholar 

  49. Hansen, J.L. et al. The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol. Cell 10, 117–128 (2002).

    CAS  PubMed  Google Scholar 

  50. Hansen, J.L., Moore, P.B. & Steitz, T.A. Structures of five antibiotics bound at the peptidyl transferase center of the large ribosomal subunit. J. Mol. Biol. 330, 1061–1075 (2003).

    CAS  PubMed  Google Scholar 

  51. Sutcliffe, J.A. Improving on nature: antibiotics that target the ribosome. Curr. Opin. Microbiol. 8, 534–542 (2005).

    CAS  PubMed  Google Scholar 

  52. Tu, D., Blaha, G., Moore, P.B. & Steitz, T.A. Structures of MLSBK antibiotics bound to mutated large ribosomal subunits provide a structural explanation for resistance. Cell 121, 257–270 (2005).

    CAS  PubMed  Google Scholar 

  53. Kohli, R.M. & Walsh, C.T. Enzymology of acyl chain macrocyclization in natural product biosynthesis. Chem. Commun. (Camb.) Feb. 7, 297–307 (2003).

  54. Walsh, C.T. Polyketide and nonribosomal peptide antibiotics: modularity and versatility. Science 303, 1805–1810 (2004).

    CAS  PubMed  Google Scholar 

  55. Miao, V. et al. The lipopeptide antibiotic A54145 biosynthetic gene cluster from Streptomyces fradiae. J. Ind. Microbiol. Biotechnol. 33, 129–140 (2006).

    CAS  PubMed  Google Scholar 

  56. Miao, V. et al. Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry. Microbiology 151, 1507–1523 (2005).

    CAS  PubMed  Google Scholar 

  57. Miao, V. et al. Genetic engineering in Streptomyces roseosporus to produce hybrid lipopeptide antibiotics. Chem. Biol. 13, 269–276 (2006).

    CAS  PubMed  Google Scholar 

  58. Baltz, R.H., Miao, V. & Wrigley, S.K. Natural products to drugs: daptomycin and related lipopeptide antibiotics. Nat. Prod. Rep. 22, 717–741 (2005).

    CAS  PubMed  Google Scholar 

  59. Brotz-Oesterhelt, H. et al. Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat. Med. 11, 1082–1087 (2005).

    PubMed  Google Scholar 

  60. Michel, K.H. & Kastner, R.E. A54556 antibiotics and process for production thereof. US patent 4492650 (1985).

  61. Joshi, S.A., Hersch, G.L., Baker, T.A. & Sauer, R.T. Communication between ClpX and ClpP during substrate processing and degradation. Nat. Struct. Mol. Biol. 11, 404–411 (2004).

    CAS  PubMed  Google Scholar 

  62. Andries, K. et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223–227 (2005).

    CAS  PubMed  Google Scholar 

  63. Wigley, D.B. Structure and mechanism of DNA topoisomerases. Annu. Rev. Biophys. Biomol. Struct. 24, 185–208 (1995).

    CAS  PubMed  Google Scholar 

  64. Wigley, D.B., Davies, G.J., Dodson, E.J., Maxwell, A. & Dodson, G. Crystal structure of an N-terminal fragment of the DNA gyrase B protein. Nature 351, 624–629 (1991).

    CAS  PubMed  Google Scholar 

  65. Zhang, Y.M., White, S.W. & Rock, C.O. Inhibiting bacterial fatty acid synthesis. J. Biol. Chem. 281, 17541–17544 (2006).

    CAS  PubMed  Google Scholar 

  66. Wang, J. et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature 441, 358–361 (2006).

    CAS  PubMed  Google Scholar 

  67. Pohlmann, J. et al. Pyrrolidinedione derivatives as antibacterial agents with a novel mode of action. Bioorg. Med. Chem. Lett. 15, 1189–1192 (2005).

    CAS  PubMed  Google Scholar 

  68. Freiberg, C., Fischer, H.P. & Brunner, N.A. Discovering the mechanism of action of novel antibacterial agents through transcriptional profiling of conditional mutants. Antimicrob. Agents Chemother. 49, 749–759 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Freiberg, C. et al. Identification and characterization of the first class of potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity. J. Biol. Chem. 279, 26066–26073 (2004).

    CAS  PubMed  Google Scholar 

  70. Breukink, E. & de Kruijff, B. Lipid II as a target for antibiotics. Nat. Rev. Drug Discov. 5, 321–332 (2006).

    CAS  PubMed  Google Scholar 

  71. Chatterjee, C. et al. Lacticin 481 synthetase phosphorylates its substrate during lantibiotic production. J. Am. Chem. Soc. 127, 15332–15333 (2005).

    CAS  PubMed  Google Scholar 

  72. Kahne, D., Leimkuhler, C., Lu, W. & Walsh, C. Glycopeptide and lipoglycopeptide antibiotics. Chem. Rev. 105, 425–448 (2005).

    CAS  PubMed  Google Scholar 

  73. He, H. et al. Mannopeptimycin esters and carbonates, potent antibiotic agents against drug-resistant bacteria. Bioorg. Med. Chem. Lett. 14, 279–282 (2004).

    CAS  PubMed  Google Scholar 

  74. Ruzin, A. et al. Mechanism of action of the mannopeptimycins, a novel class of glycopeptide antibiotics active against vancomycin-resistant gram-positive bacteria. Antimicrob. Agents Chemother. 48, 728–738 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Magarvey, N.A., Haltli, B., He, M., Greenstein, M. & Hucul, J.A. Biosynthetic pathway for mannopeptimycins, lipoglycopeptide antibiotics active against drug-resistant gram-positive pathogens. Antimicrob. Agents Chemother. 50, 2167–2177 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Walker, S. et al. Chemistry and biology of ramoplanin: a lipoglycodepsipeptide with potent antibiotic activity. Chem. Rev. 105, 449–476 (2005).

    CAS  PubMed  Google Scholar 

  77. Patton, G.C. & van der Donk, W.A. New developments in lantibiotic biosynthesis and mode of action. Curr. Opin. Microbiol. 8, 543–551 (2005).

    CAS  PubMed  Google Scholar 

  78. Wiedemann, I. et al. Specific binding of nisin to the peptidoglycan precursor lipid II combines pore formation and inhibition of cell wall biosynthesis for potent antibiotic activity. J. Biol. Chem. 276, 1772–1779 (2001).

    CAS  PubMed  Google Scholar 

  79. Li, B. et al. Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis. Science 311, 1464–1467 (2006).

    CAS  PubMed  Google Scholar 

  80. Xie, L. et al. Lacticin 481: in vitro reconstitution of lantibiotic synthetase activity. Science 303, 679–681 (2004).

    CAS  PubMed  Google Scholar 

  81. Hsu, S.T. et al. The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics. Nat. Struct. Mol. Biol. 11, 963–967 (2004).

    CAS  PubMed  Google Scholar 

  82. Holtzel, A. et al. Arylomycins A and B, new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tu 6075. II. Structure elucidation. J. Antibiot. (Tokyo) 55, 571–577 (2002).

    CAS  Google Scholar 

  83. Schimana, J. et al. Arylomycins A and B, new biaryl-bridged lipopeptide antibiotics produced by Streptomyces sp. Tu 6075. I. Taxonomy, fermentation, isolation and biological activities. J. Antibiot. (Tokyo) 55, 565–570 (2002).

    CAS  Google Scholar 

  84. Kulanthaivel, P. et al. Novel lipoglycopeptides as inhibitors of bacterial signal peptidase I. J. Biol. Chem. 279, 36250–36258 (2004).

    CAS  PubMed  Google Scholar 

  85. Paetzel, M., Goodall, J.J., Kania, M., Dalbey, R.E. & Page, M.G. Crystallographic and biophysical analysis of a bacterial signal peptidase in complex with a lipopeptide-based inhibitor. J. Biol. Chem. 279, 30781–30790 (2004).

    CAS  PubMed  Google Scholar 

  86. Bister, B. et al. Abyssomicin C-A polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor of the p-aminobenzoic acid/tetrahydrofolate biosynthesis pathway. Angew. Chem. Int. Edn Engl. 43, 2574–2576 (2004).

    CAS  Google Scholar 

  87. Zapf, C.W., Harrison, B.A., Drahl, C. & Sorensen, E.J.A. Diels-Alder macrocyclization enables an efficient asymmetric synthesis of the antibacterial natural product abyssomicin C. Angew. Chem. Int. Edn Engl. 44, 6533–6537 (2005).

    CAS  Google Scholar 

  88. Clardy, J. & Walsh, C. Lessons from natural molecules. Nature 432, 829–837 (2004).

    CAS  PubMed  Google Scholar 

  89. Robertson, D.E. et al. Exploring nitrilase sequence space for enantioselective catalysis. Appl. Environ. Microbiol. 70, 2429–2436 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Research in the authors' laboratories is supported by US National Institutes of Health grants CA24487 and CA59021 (to J.C.) and GM20011 and GM49338 (to C.T.W.). M.A.F. is supported by a fellowship from the Hertz Foundation.

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Correspondence to Christopher T Walsh.

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Christopher T. Walsh is on the board of directors of Kosan Biosciences, and Jon Clardy is on the scientific advisory boards on Novobiotics and Makoto Biosciences.

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Clardy, J., Fischbach, M. & Walsh, C. New antibiotics from bacterial natural products. Nat Biotechnol 24, 1541–1550 (2006). https://doi.org/10.1038/nbt1266

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