Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Comprehensive analysis of biosynthetic gene clusters in bacteria and discovery of Tumebacillus as a potential producer of natural products

The Journal of Antibiotics volume 76, pages 316–323 (2023)Cite this article

Subjects

Abstract

Limited microbial genera such as Streptomyces have served as sources of natural products (NPs), whereas most others have been less investigated. The vast accumulation of genomic data available in the NCBI database enables us to bioinformatically estimate the ability of other microbial groups to produce NPs. We analyzed 21,052 complete bacterial genome sequences using antiSMASH and compared the average numbers of biosynthetic gene clusters (BGCs) related to polyketides, non-ribosomal peptides, and/or terpenes biosynthesis at the genus level. Our bioinformatic analyses showed that Tumebacillus has 5–15 BGCs and is a promising NP producer. We searched for NPs from the culture broth of Tumebacillus permanentifrigoris JCM 14557T and found two novel compounds (tumebacin with anti-Bacillus activity and tumepyrazine) and identified two known compounds. Our results highlight the diversity of sources of NPs awaiting discovery.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83:770–803.

    Article  CAS  PubMed  Google Scholar 

  2. Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov. 2021;20:200–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bérdy J. Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot. 2012;65:385–95.

    Article  Google Scholar 

  4. Pidot SJ, Coyne S, Kloss F, Hertweck C. Antibiotics from neglected bacterial sources. Int J Med Microbiol. 2014;304:14–22.

    Article  CAS  PubMed  Google Scholar 

  5. Müller R, Wink J. Future potential for anti-infectives from bacteria—how to exploit biodiversity and genomic potential. Int J Med Microbiol. 2014;304:3–13.

    Article  PubMed  Google Scholar 

  6. Hoffmann T, Krug D, Bozkurt N, Duddela S, Jansen R, Garcia R, et al. Correlating chemical diversity with taxonomic distance for discovery of natural products in myxobacteria. Nat Commun. 2018;9:803.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Medema MH, Kottmann R, Yilmaz P, Cummings M, Biggins JB, Blin K, et al. Minimum information about a biosynthetic gene cluster. Nat Chem Biol. 2015;11:625–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ueoka R, Bhushan A, Probst SI, Bray WM, Lokey RS, Linington RG, et al. Genome-based identification of a plant-associated marine bacterium as a rich natural product source. Angew Chem Int Ed. 2018;57:14519–23.

    Article  CAS  Google Scholar 

  9. Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, et al. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 2011;39:W339–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blin K, Shaw S, Steinke K, Villebro R, Ziemert N, Lee SY, et al. antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res. 2019;47:W81–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Steven B, Chen MQ, Greer CW, Whyte LG, Niederberger TD. Tumebacillus permanentifrigoris gen. nov., sp. nov., an aerobic, spore-forming bacterium isolated from Canadian high Arctic permafrost. Int J Syst Evol Microbiol. 2008;58:1497–501.

    Article  CAS  PubMed  Google Scholar 

  12. Baek SH, Cui Y, Kim SC, Cui CH, Yin C, Lee ST, et al. Tumebacillus ginsengisoli sp. nov., isolated from soil of a ginseng field. Int J Syst Evol Microbiol. 2011;61:1715–9.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Q, Xie N, Qin Y, Shen N, Zhu J, Mi H, et al. Tumebacillus flagellatus sp. nov., an α-amylase/pullulanase-producing bacterium isolated from cassava wastewater. Int J Syst Evol Microbiol. 2013;63:3138–42.

    Article  CAS  PubMed  Google Scholar 

  14. Her J, Srinivasan S, Lee SS. Tumebacillus luteolus sp. nov., isolated from soil. Int J Syst Evol Microbiol. 2015;65:4107–12.

    Article  CAS  PubMed  Google Scholar 

  15. Prasad RV, Bhumika V, Anil Kumar P, Srinivas NRT. Tumebacillus lipolyticus sp. nov., isolated from river water. Int J Syst Evol Microbiol. 2015;65:4363–8.

    Article  CAS  PubMed  Google Scholar 

  16. Wu YF, Zhang B, Xing P, Wu QL, Liu SJ. Tumebacillus algifaecis sp. nov., isolated from decomposing algal scum. Int J Syst Evol Microbiol. 2015;65:2194–8.

    Article  CAS  PubMed  Google Scholar 

  17. Kim JH, Kim W. Tumebacillus soli sp. nov., isolated from non-rhizosphere soil. Int J Syst Evol Microbiol. 2016;66:2192–7.

    Article  CAS  PubMed  Google Scholar 

  18. Sung H, Kim HS, Lee JY, Kang W, Kim PS, Hyun DW, et al. Tumebacillus avium sp. nov., isolated from the gut of a cinereous vulture, Aegypius monachus. Int J Syst Evol Microbiol. 2018;68:1659–64.

    Article  CAS  PubMed  Google Scholar 

  19. Kang M, Chhetri G, Kim J, Kim I, So Y, Seo T. Tumebacillus amylolyticus sp. nov., isolated from garden soil in Korea. Int J Syst Evol Microbiol. 2022;72:005376.

    Article  CAS  Google Scholar 

  20. Hanawa F, Tahara S, Towers GHN. Antifungal nitro compounds from Skunk Cabbage (Lysichitum americanum) leaves treated with cupric chloride. Phytochemistry. 2000;53:55–8.

    Article  CAS  PubMed  Google Scholar 

  21. Li S, Wu X, Zhang L, Shen Y, Du L. Activation of a cryptic gene cluster in Lysobacter enzymogenes reveals a module/domain portable mechanism of nonribosomal peptide synthetases in the biosynthesis of pyrrolopyrazines. Org Lett. 2017;19:5010–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clark K, Karsch-Mizrachi I, Lipman DJ, Ostell J, Sayers EW. GenBank. Nucleic Acids Res. 2016;44:D67–72.

    Article  CAS  PubMed  Google Scholar 

  23. Eloff J. A sensitive and quick microplate method to determine the minimal inhibitory concentration of plant extracts for bacteria. Planta Med. 1998;64:711–3.

    Article  CAS  PubMed  Google Scholar 

  24. Weinstein MP, Lewis II JS, Bobenchik AM, Campeau S, Cullen SK, Galas MF, et al. Performance standards for antimicrobial susceptibility testing. M100 30th ed. Wayne: Clinical and Laboratory Standards Institute; 2020.

  25. Dictionary of natural products on DVD. Boca Raton: CRC Press, LLC; 2016.

  26. Ikeda H, Matsumori N, Ono M, Suzuki A, Isogai A, Nagasawa H, et al. Absolute configuration of aflastatin A, a specific inhibitor of aflatoxin production by Aspergillus parasiticus. J Org Chem. 2000;65:438–44.

    Article  CAS  PubMed  Google Scholar 

  27. Michael AP, Grace EJ, Kotiw M, Barrow RA. Ravenic acid, a new tetramic acid isolated from a cultured microfungus, Penicillium sp. J Nat Prod. 2002;65:1360–2.

    Article  CAS  PubMed  Google Scholar 

  28. Ratnayake AS, Davis RA, Harper MK, Veltri CA, Andjelic CD, Barrows LR, et al. Aurantosides G, H, and I: three new tetramic acid glycosides from a papua new guinea Theonella s winhoei. J Nat Prod. 2005;68:104–7.

    Article  CAS  PubMed  Google Scholar 

  29. Rutledge PJ, Challis GL. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat Rev Microbiol. 2015;13:509–23.

    Article  CAS  PubMed  Google Scholar 

  30. Baral B, Akhgari A, Metsä-Ketelä M. Activation of microbial secondary metabolic pathways: avenues and challenges. Synth Syst Biotechnol. 2018;3:163–78.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Distinguished Emeritus Professor Satoshi Ōmura (Kitasato University) for his helpful support and valuable guidance and suggestions. We are grateful to Dr. Kenichiro Nagai and Ms. Noriko Sato (School of Pharmacy, Kitasato University) for the mass and NMR spectral measurements. This study was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) of the Japan Agency for Medical Research and Development (AMED) under Grant Numbers JP19am0101096 and JP22ama121035.

Author information

Authors and Affiliations

  1. Graduate School of Infection Control Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Yuta Kikuchi, Masato Iwatsuki, Aoi Kimishima, Hayama Tsutsumi, Yukihiro Asami & Yuki Inahashi

  2. Graduate School of Science, Kitasato University, 1-15-1, Kitazato, Minami, Sagamihara, Kanagawa, 252-0373, Japan

    Miku Kawashima

  3. Ōmura Satoshi Memorial Institute, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan

    Masato Iwatsuki, Aoi Kimishima, Hayama Tsutsumi, Yukihiro Asami & Yuki Inahashi

Authors
  1. Yuta Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miku Kawashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masato Iwatsuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aoi Kimishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hayama Tsutsumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yukihiro Asami
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuki Inahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuki Inahashi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kikuchi, Y., Kawashima, M., Iwatsuki, M. et al. Comprehensive analysis of biosynthetic gene clusters in bacteria and discovery of Tumebacillus as a potential producer of natural products. J Antibiot 76, 316–323 (2023). https://doi.org/10.1038/s41429-023-00609-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-023-00609-y

Search

Advanced search

Quick links