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Natural products from anaerobes

  • Jeffrey S. Li
  • Colin Charles Barber
  • Wenjun Zhang
Natural Products - Original Paper

Abstract

Natural product discovery in the microbial world has historically been biased toward aerobes. Recent in silico analysis demonstrates that genomes of anaerobes encode unexpected biosynthetic potential for natural products, however, chemical data on natural products from the anaerobic world are extremely limited. Here, we review the current body of work on natural products isolated from strictly anaerobic microbes, including recent genome mining efforts to discover polyketides and non-ribosomal peptides from anaerobes. These known natural products of anaerobes have demonstrated interesting molecular scaffolds, biosynthetic logic, and/or biological activities, making anaerobes a promising reservoir for future natural product discovery.

Keywords

Secondary metabolite Anaerobic organism Genome mining Antibiotic 

Notes

Acknowledgements

This work was financially supported by the Energy Biosciences Institute, Alfred P. Sloan Foundation, the National Institutes of Health (DP2AT009148), and the Chan Zuckerberg Biohub Investigator Program.

References

  1. 1.
    Abken HJ, Tietze M, Brodersen J et al (1998) Isolation and characterization of methanophenazine and function of phenazines in membrane-bound electron transport of Methanosarcina mazei Gö1. J Bacteriol 180:2027–2032PubMedPubMedCentralGoogle Scholar
  2. 2.
    Alsaker KV, Papoutsakis ET (2005) Transcriptional program of early sporulation and stationary-phase events in Clostridium acetobutylicum. J Bacteriol 187:7103–7118.  https://doi.org/10.1128/JB.187.20.7103-7118.2005 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Andrianasolo EH, Haramaty L, Rosario-Passapera R et al (2009) Ammonificins A and B, hydroxyethylamine chroman derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans. J Nat Prod 72:1216–1219.  https://doi.org/10.1021/np800726d CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Andrianasolo EH, Haramaty L, Rosario-Passapera R et al (2012) Ammonificins C and D, hydroxyethylamine chromene derivatives from a cultured marine hydrothermal vent bacterium, Thermovibrio ammonificans. Mar Drugs 10:2300–2311.  https://doi.org/10.3390/md10102300 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Baltz RH (2017) Gifted microbes for genome mining and natural product discovery. J Ind Microbiol Biotechnol 44:573–588.  https://doi.org/10.1007/s10295-016-1815-x CrossRefPubMedGoogle Scholar
  6. 6.
    Baltz RH (2017) Molecular beacons to identify gifted microbes for genome mining. J Antibiot 70:639–646.  https://doi.org/10.1038/ja.2017.1 CrossRefPubMedGoogle Scholar
  7. 7.
    Baltz RH (2018) Synthetic biology, genome mining, and combinatorial biosynthesis of NRPS-derived antibiotics: a perspective. J Ind Microbiol Biotechnol 45:635–649.  https://doi.org/10.1007/s10295-017-1999-8 CrossRefGoogle Scholar
  8. 8.
    Behnken S, Hertweck C (2012) Anaerobic bacteria as producers of antibiotics. Appl Microbiol Biotechnol 96:61–67.  https://doi.org/10.1007/s00253-012-4285-8 CrossRefPubMedGoogle Scholar
  9. 9.
    Behnken S, Lincke T, Kloss F et al (2012) Antiterminator-mediated unveiling of cryptic polythioamides in an anaerobic bacterium. Angew Chemie Int Ed 51:2425–2428.  https://doi.org/10.1002/anie.201108214 CrossRefGoogle Scholar
  10. 10.
    Beifuss U, Tietze M (2005) Methanophenazine and other natural biologically active phenazines. In: Mulzer J (ed) Natural products synthesis II. Topics in current chemistry, vol 244. Springer, Berlin, pp 77–113.  https://doi.org/10.1007/b96889 Google Scholar
  11. 11.
    Beifuss U, Tietze M, Bäumer S, Deppenmeier U (2000) Methanophenazine: structure, total synthesis, and function of a new cofactor from methanogenic archaea. Angew Chemie Int Ed 39:2470–2472.  https://doi.org/10.1002/1521-3773(20000717)39:14%3c2470:AID-ANIE2470%3e3.0.CO;2-R CrossRefGoogle Scholar
  12. 12.
    Blankenfeldt W, Parsons JF (2014) The structural biology of phenazine biosynthesis. Curr Opin Struct Biol 29:26–33.  https://doi.org/10.1016/J.SBI.2014.08.013 CrossRefPubMedGoogle Scholar
  13. 13.
    Blin K, Wolf T, Chevrette MG et al (2017) antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification. Nucl Acids Res 45:W36–W41.  https://doi.org/10.1093/nar/gkx319 CrossRefPubMedGoogle Scholar
  14. 14.
    Challinor VL, Bode HB (2015) Bioactive natural products from novel microbial sources. Ann NY Acad Sci 1354:82–97.  https://doi.org/10.1111/nyas.12954 CrossRefPubMedGoogle Scholar
  15. 15.
    Chiriac AI, Kloss F, Krämer J et al (2015) Mode of action of closthioamide: the first member of the polythioamide class of bacterial DNA gyrase inhibitors. J Antimicrob Chemother 70:2576–2588.  https://doi.org/10.1093/jac/dkv161 CrossRefPubMedGoogle Scholar
  16. 16.
    Dabard J, Bridonneau C, Phillipe C et al (2001) Ruminococcin A, a new lantibiotic produced by a Ruminococcus gnavus strain isolated from human feces. Appl Environ Microbiol 67:4111–4118.  https://doi.org/10.1128/AEM.67.9.4111-4118.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ding C, Wu X, Auckloo B et al (2016) An unusual stress metabolite from a hydrothermal vent fungus Aspergillus sp. WU 243 induced by cobalt. Molecules 21:105.  https://doi.org/10.3390/molecules21010105 CrossRefPubMedGoogle Scholar
  18. 18.
    Donia MS, Cimermancic P, Schulze CJ et al (2014) A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 158:1402–1414.  https://doi.org/10.1016/J.CELL.2014.08.032 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Dunbar K, Büttner H, Molloy E, Dell M, Kumpfmueller J, Hertweck C (2018) Genome editing reveals novel thiotemplated assembly of polythioamide antibiotics in anaerobic bacteria. Angew Chem Int Ed.  https://doi.org/10.1002/anie.201807970 CrossRefGoogle Scholar
  20. 20.
    Ezaki M, Muramatsu H, Takase S et al (2008) Naphthalecin, a novel antibiotic produced by the anaerobic bacterium Sporotalea colonica sp. nov. J Antibiot (Tokyo) 61:207–212.  https://doi.org/10.1038/ja.2008.30 CrossRefGoogle Scholar
  21. 21.
    Fajardo A, Martínez JL (2008) Antibiotics as signals that trigger specific bacterial responses. Curr Opin Microbiol 11:161–167.  https://doi.org/10.1016/j.mib.2008.02.006 CrossRefPubMedGoogle Scholar
  22. 22.
    Gonzalez DJ, Lee SW, Hensler ME et al (2010) Clostridiolysin S, a post-translationally modified biotoxin from Clostridium botulinum. J Biol Chem 285:28220–28228.  https://doi.org/10.1074/jbc.M110.118554 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Guo C-J, Chang F-Y, Wyche TP et al (2017) Discovery of reactive microbiota-derived metabolites that inhibit host proteases. Cell 168(517–526):e18.  https://doi.org/10.1016/J.CELL.2016.12.021 CrossRefGoogle Scholar
  24. 24.
    Guttenberger N, Blankenfeldt W, Breinbauer R (2017) Recent developments in the isolation, biological function, biosynthesis, and synthesis of phenazine natural products. Bioorg Med Chem 25:6149–6166.  https://doi.org/10.1016/J.BMC.2017.01.002 CrossRefPubMedGoogle Scholar
  25. 25.
    Hans-Hartwig O, Schirmeister T (1997) Cysteine proteases and their inhibitors. Chem Rev 97:133–172.  https://doi.org/10.1021/CR950025U CrossRefGoogle Scholar
  26. 26.
    Herman NA, Kim SJ, Li JS et al (2017) The industrial anaerobe Clostridium acetobutylicum uses polyketides to regulate cellular differentiation. Nat Commun 8:1514.  https://doi.org/10.1038/s41467-017-01809-5 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Konno H (2012) Synthesis of bioactive natural products as protein inhibitors. Biosci Biotechnol Biochem 76:1257–1261CrossRefGoogle Scholar
  28. 28.
    Letzel A-C, Pidot SJ, Hertweck C (2013) A genomic approach to the cryptic secondary metabolome of the anaerobic world. Nat Prod Rep 30:392–428.  https://doi.org/10.1039/C2NP20103H CrossRefPubMedGoogle Scholar
  29. 29.
    Letzel A-C, Pidot SJ, Hertweck C (2014) Genome mining for ribosomally synthesized and post-translationally modified peptides (RiPPs) in anaerobic bacteria. BMC Genomics 15:983.  https://doi.org/10.1186/1471-2164-15-983 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Lincke T, Behnken S, Ishida K et al (2010) Closthioamide: an unprecedented polythioamide antibiotic from the strictly anaerobic bacterium Clostridium cellulolyticum. Angew Chemie 122:2055–2057.  https://doi.org/10.1002/ange.200906114 CrossRefGoogle Scholar
  31. 31.
    Lütke-Eversloh T, Bahl H (2011) Metabolic engineering of Clostridium acetobutylicum: recent advances to improve butanol production. Curr Opin Biotechnol 22:634–647.  https://doi.org/10.1016/J.COPBIO.2011.01.011 CrossRefPubMedGoogle Scholar
  32. 32.
    Miari VF, Solanki P, Hleba Y et al (2017) In vitro susceptibility to closthioamide among clinical and reference strains of Neisseria gonorrhoeae. Antimicrob Agents Chemother 61:e00929-17.  https://doi.org/10.1128/AAC.00929-17 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661.  https://doi.org/10.1021/acs.jnatprod.5b01055 CrossRefGoogle Scholar
  34. 34.
    O’Brien J, Wright GD (2011) An ecological perspective of microbial secondary metabolism. Curr Opin Biotechnol 22:552–558.  https://doi.org/10.1016/J.COPBIO.2011.03.010 CrossRefPubMedGoogle Scholar
  35. 35.
    Paredes CJ, Alsaker KV, Papoutsakis ET (2005) A comparative genomic view of clostridial sporulation and physiology. Nat Rev Microbiol 3:969–978.  https://doi.org/10.1038/nrmicro1288 CrossRefPubMedGoogle Scholar
  36. 36.
    Petitdemange E, Caillet F, Giallo J, Gaudin C (1984) Clostridium cellulolyticum sp. nov., a cellulolytic, mesophilic species from decayed grass. Int J Syst Bacteriol 34:155–159CrossRefGoogle Scholar
  37. 37.
    Pidot S, Ishida K, Cyrulies M, Hertweck C (2014) Discovery of clostrubin, an exceptional polyphenolic polyketide antibiotic from a strictly anaerobic bacterium. Angew Chemie Int Ed 53:7856–7859.  https://doi.org/10.1002/anie.201402632 CrossRefGoogle Scholar
  38. 38.
    Powers JC, Asgian JL, Asgian Ekici OD, Özlem Doǧan Ekici A, James KE (2002) Irreversible inhibitors of serine, cysteine, and threonine proteases. Chem Rev 102:4639–4750.  https://doi.org/10.1021/CR010182V CrossRefPubMedGoogle Scholar
  39. 39.
    Price-Whelan A, Dietrich LEP, Newman DK (2006) Rethinking “secondary” metabolism: physiological roles for phenazine antibiotics. Nat Chem Biol 2:71–78.  https://doi.org/10.1038/nchembio764 CrossRefPubMedGoogle Scholar
  40. 40.
    Raaijmakers JM, Mazzola M (2012) Diversity and natural functions of antibiotics produced by beneficial and plant pathogenic bacteria. Annu Rev Phytopathol 50:403–424.  https://doi.org/10.1146/annurev-phyto-081211-172908 CrossRefPubMedGoogle Scholar
  41. 41.
    Rischer M, Raguž L, Guo H et al (2018) Biosynthesis, synthesis, and activities of barnesin A, a NRPS-PKS hybrid produced by an anaerobic epsilonproteobacterium. ACS Chem Biol Article ASAP.  https://doi.org/10.1021/acschembio.8b00445 CrossRefGoogle Scholar
  42. 42.
    Schneider BA, Balskus EP (2018) Discovery of small molecule protease inhibitors by investigating a widespread human gut bacterial biosynthetic pathway. Tetrahedron 74:3215–3230.  https://doi.org/10.1016/J.TET.2018.03.043 CrossRefGoogle Scholar
  43. 43.
    Shabuer G, Ishida K, Pidot SJ et al (2015) Plant pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory. Science 350:670–674.  https://doi.org/10.1126/science.aac9990 CrossRefPubMedGoogle Scholar
  44. 44.
    Shi Y, Pan C, Auckloo BN et al (2017) Stress-driven discovery of a cryptic antibiotic produced by Streptomyces sp. WU20 from Kueishantao hydrothermal vent with an integrated metabolomics strategy. Appl Microbiol Biotechnol 101:1395–1408.  https://doi.org/10.1007/s00253-016-7823-y CrossRefPubMedGoogle Scholar
  45. 45.
    Siklos M, BenAissa M, Thatcher GRJ (2015) Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors. Acta Pharm Sin B 5:506–519.  https://doi.org/10.1016/J.APSB.2015.08.001 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sturgen NO, Casida LE Jr (1962) Antibiotic production by anaerobic bacteria. Appl Microbiol 10:55–59PubMedPubMedCentralGoogle Scholar
  47. 47.
    Vetriani C, Speck MD, Ellor SV et al (2004) Thermovibrio ammonificans sp. nov., a thermophilic, chemolithotrophic, nitrate-ammonifying bacterium from deep-sea hydrothermal vents. Int J Syst Evol Microbiol 54:175–181.  https://doi.org/10.1099/ijs.0.02781-0 CrossRefPubMedGoogle Scholar
  48. 48.
    Westerik JO, Wolfenden R (1972) Aldehydes as inhibitors of papain. J Biol Chem 247:8195–8197PubMedGoogle Scholar
  49. 49.
    Woo J-T, Sigeizumi S, Yamaguchi K et al (1995) Peptidyl aldehyde derivatives as potent and selective inhibitors of cathepsin L. Bioorg Med Chem Lett 5:1501–1504CrossRefGoogle Scholar
  50. 50.
    Zhu B, Wang X, Li L (2010) Human gut microbiome: the second genome of human body. Protein Cell 1:718–725.  https://doi.org/10.1007/s13238-010-0093-z CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Ziemert N, Alanjary M, Weber T (2016) The evolution of genome mining in microbes—a review. Nat Prod Rep 33:988–1005.  https://doi.org/10.1039/C6NP00025H CrossRefPubMedGoogle Scholar

Copyright information

© Society for Industrial Microbiology and Biotechnology 2018

Authors and Affiliations

  1. 1.Department of Chemical and Biomolecular EngineeringUniversity of California BerkeleyBerkeleyUSA
  2. 2.Department of Plant and Microbial BiologyUniversity of California BerkeleyBerkeleyUSA
  3. 3.Chan Zuckerberg BiohubSan FranciscoUSA

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