Skip to main content
SpringerLink
Log in

A Novel Finding: 2,4-Di-tert-butylphenol from Streptomyces bacillaris ANS2 Effective Against Mycobacterium tuberculosis and Cancer Cell Lines

  • Original Article
  • Published:
Applied Biochemistry and Biotechnology Aims and scope Submit manuscript

Abstract

The aim of the present study is to identify actinobacteria Streptomyces bacillaris ANS2 as the source of the potentially beneficial compound 2,4-di-tert-butylphenol, describe its chemical components, and assess its anti-tubercular (TB) and anti-cancer properties. Ethyl acetate was used in the agar surface fermentation of S. bacillaris ANS2 to produce the bioactive metabolites. Using various chromatographic and spectroscopy analyses, the potential bioactive metabolite separated and identified as 2,4-di-tert-butylphenol (2,4-DTBP). The lead compound 2,4-DTBP inhibited 78% and 74% of relative light unit (RLU) decrease against MDR Mycobacterium tuberculosis at 100ug/ml and 50ug/ml concentrations, respectively. The Wayne model was used to assess the latent/dormant potential in M. tuberculosis H37RV at various doses, and the MIC for the isolated molecule was found to be 100ug/ml. Furthermore, the molecular docking of 2,4-DTBP was docked using Autodock Vinasuite onto the substrate binding site of the target Mycobacterium lysine aminotransferase (LAT) and the grid box was configured for the docking run to cover the whole LAT dimer interface. At a dosage of 1 mg/ml, the anti-cancer activity of the compound 2,4-DTBP was 88% and 89% inhibited against the HT 29 (colon cancer) and HeLa (cervical cancer) cell lines. According to our literature survey, this present finding may be the first report on anti-TB activity of 2,4-DTBP and has the potential to become an effective natural source and the promising pharmaceutical drug in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The data used to support the findings of this study are available from the corresponding authors upon request.

References

  1. WHO. Global tuberculosis report 2022; https://www.who.int/publications/i/item/9789240061729. accessed 04.01.2023

  2. Ho, L. J., Yang, H. Y., Chung, C. H., Chang, W. C., Yang, S. S., Sun, C. A., Chien, W. C., & Su, R. Y. (2021). Increased risk of secondary lung cancer in patients with tuberculosis: A nationwide, population-based cohort study. PloS one, 16(5), e0250531. https://doi.org/10.1371/journal.pone.0250531

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Xiang, Y., Huang, C., He, Y., & Zhang, Q. (2021). Cancer or tuberculosis: A comprehensive review of the clinical and imaging features in diagnosis of the confusing mass. Frontiers in Oncology, 11, 644150. https://doi.org/10.3389/fonc.2021.644150

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Chen, G. L., Guo, L., Yang, S., & Ji, D. M. (2021). Cancer risk in tuberculosis patients in a high endemic area. BMC Cancer, 21(1), 679. https://doi.org/10.1186/s12885-021-08391-6

    Article  PubMed  PubMed Central  Google Scholar 

  5. Atanasov, A. G., Zotchev, S. B., Dirsch, V. M., International Natural Product Sciences Taskforce, & Supuran, C. T. (2021). Natural products in drug discovery: Advances and opportunities. Nature Reviews. Drug Discovery, 20(3), 200–216. https://doi.org/10.1038/s41573-020-00114-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Selim, M., Abdelhamid, S. A., & Mohamed, S. S. (2021). Secondary metabolites and biodiversity of actinomycetes. Journal, Genetic Engineering & Biotechnology, 19(1), 72. https://doi.org/10.1186/s43141-021-00156-9

    Article  Google Scholar 

  7. Al-Dhabi, N. A., Esmail, G. A., Duraipandiyan, V., ValanArasu, M., & Salem-Bekhit, M. M. (2016). Isolation, identification and screening of antimicrobial thermophilic Streptomyces sp. Al-Dhabi-1 isolated from Tharban hot spring, Saudi Arabia. Extremophiles: life under extreme conditions, 20(1), 79–90. https://doi.org/10.1007/s00792-015-0799-1

    Article  PubMed  CAS  Google Scholar 

  8. Al-Dhabi, N. A., Esmail, G. A., Duraipandiyan, V., & Arasu, M. V. (2019). Chemical profiling of Streptomyces sp. Al-Dhabi-2 recovered from an extreme environment in Saudi Arabia as a novel drug source for medical and industrial applications. Saudi Journal of Biological Sciences, 26(4), 758–766. https://doi.org/10.1016/j.sjbs.2019.03.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Valsalam, S., Agastian, P., Arasu, M. V., Al-Dhabi, N. A., Ghilan, A. M., Kaviyarasu, K., Ravindran, B., Chang, S. W., & Arokiyaraj, S. (2019). Rapid biosynthesis and characterization of silver nanoparticles from the leaf extract of Tropaeolum majus L. and its enhanced in-vitro antibacterial, antifungal, antioxidant and anticancer properties. Journal of Photochemistry and Photobiology B, Biology, 191, 65–74. https://doi.org/10.1016/j.jphotobiol.2018.12.010

    Article  PubMed  CAS  Google Scholar 

  10. Arasu, M. V., Arokiyaraj, S., Viayaraghavan, P., Kumar, T., Duraipandiyan, V., Al-Dhabi, N. A., & Kaviyarasu, K. (2019). One step green synthesis of larvicidal, and azo dye degrading antibacterial nanoparticles by response surface methodology. Journal of Photochemistry and Photobiology B, Biology, 190, 154–162. https://doi.org/10.1016/j.jphotobiol.2018.11.020

    Article  PubMed  CAS  Google Scholar 

  11. Bu, Y. Y., Yamazaki, H., Ukai, K., & Namikoshi, M. (2014). Anti-mycobacterial nucleoside antibiotics from a marine-derived Streptomyces sp. TPU1236A. Marine Drugs, 12(12), 6102–6112. https://doi.org/10.3390/md12126102

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Xie, Y., Chen, R., Si, S., Sun, C., & Xu, H. (2007). A new nucleosidyl-peptide antibiotic, sansanmycin. The Journal of Antibiotics, 60(2), 158–161. https://doi.org/10.1038/ja.2007.16

    Article  PubMed  CAS  Google Scholar 

  13. Igarashi, M., Nakagawa, N., Doi, N., Hattori, S., Naganawa, H., & Hamada, M. (2003). Caprazamycin B, a novel anti-tuberculosis antibiotic, from Streptomyces sp. The Journal of Antibiotics, 56(6), 580–583. https://doi.org/10.7164/antibiotics.56.580

    Article  PubMed  Google Scholar 

  14. Manigundan, K., Jerrine, J., Radhakrishnan, M., Sivarajan, A., & Balagurunathan, R. (2021). Multifaceted bioproperties of Streptomyces bacillaris ANS2 isolated from Andaman and Nicobar Islands, India. Research Journal of Biotechnology, 16(11), 99–108. https://doi.org/10.25303/1611rjbt99108

    Article  Google Scholar 

  15. Blunt, J. W., Copp, B. R., Keyzers, R. A., Munro, M. H., & Prinsep, M. R. (2016). Marine natural products. Natural Product Reports, 33(3), 382–431. https://doi.org/10.1039/c5np00156k

    Article  PubMed  CAS  Google Scholar 

  16. Zhao, F., Wang, P., Lucardi, R. D., Su, Z., & Li, S. (2020). Natural sources and bioactivities of 2,4-di-tert-butylphenol and its analogs. Toxins, 12(1), 35. https://doi.org/10.3390/toxins12010035

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Varsha, K. K., Devendra, L., Shilpa, G., Priya, S., Pandey, A., & Nampoothiri, K. M. (2015). 2,4-Di-tert-butyl phenol as the antifungal, antioxidant bioactive purified from a newly isolated Lactococcus sp. International Journal of Food Microbiology, 211, 44–50. https://doi.org/10.1016/j.ijfoodmicro.2015.06.025

    Article  PubMed  CAS  Google Scholar 

  18. Ayswarya, S., Radhakrishnan, M., Manigundan, K., Amit, K. S., Madhukar, S., & Syed, G. D. (2022). 2,4-Di-tert-butylphenol (2,4-DTBP) purified from Streptomyces sp. KCA1 from Phyllanthus niruri: Isolation, characterization, antibacterial and anticancer properties. Journal of King Saud University- Science, 34(5), 102088. https://doi.org/10.1016/j.jksus.2022.102088

    Article  Google Scholar 

  19. Chawawisit, K., Bhoopong, P., Phupong, W., & Lertcanawanichakul, M. (2015). 2,4-Ditert-butylphenol, the bioactive compound produced by Streptomyces sp. KB1. Journal of Applied Pharmaceutical Science, 5, 7–12. https://doi.org/10.7324/JAPS.2015.510.S2

    Article  CAS  Google Scholar 

  20. Chawawisit, K., Bhoopong, P., Phupong, W., & Lertcanawanichakul, M. (2015). AntiMRSA activity, mode of action and cytotoxicity of 2, 4-Di-tert-butylphenol produced by Streptomyces sp. KB1. International Journal of Pharmaceutical Sciences Review and Research, 35, 114–119.

    CAS  Google Scholar 

  21. Belghit, S., Driche, E. H., Bijani, C., Zitouni, A., Sabaou, N., Badji, B., & Mathieu, F. (2016). Activity of 2,4-di-tert-butylphenol produced by a strain of Streptomyces mutabilis isolated from a Saharan soil against Candida albicans and other pathogenic fungi. Journal de Mycologie Medicale, 26(2), 160–169. https://doi.org/10.1016/j.mycmed.2016.03.001

    Article  PubMed  CAS  Google Scholar 

  22. Yoon, M. A., Jeong, T. S., Park, D. S., Xu, M. Z., Oh, H. W., Song, K. B., Lee, W. S., & Park, H. Y. (2006). Antioxidant effects of quinoline alkaloids and 2,4-di-tert-butylphenol isolated from Scolopendra subspinipes. Biological & Pharmaceutical Bulletin, 29(4), 735–739. https://doi.org/10.1248/bpb.29.735

    Article  CAS  Google Scholar 

  23. Choi, S. J., Kim, J. K., Kim, H. K., Harris, K., Kim, C. J., Park, G. G., Park, C. S., & Shin, D. H. (2013). 2,4-Di-tert-butylphenol from sweet potato protects against oxidative stress in PC12 cells and in mice. Journal of Medicinal Food, 16(11), 977–983. https://doi.org/10.1089/jmf.2012.2739

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nair, R., Jayasree, D. V., Biju, P. G., & Baby, S. (2020). Anti-inflammatory and anticancer activities of erythrodiol-3-acetate and 2,4-di-tert-butylphenol isolated from Humboldtia unijuga. Natural Product Research, 34(16), 2319–2322. https://doi.org/10.1080/14786419.2018.1531406

    Article  PubMed  CAS  Google Scholar 

  25. Padmavathi, A. R., Abinaya, B., & Pandian, S. K. (2014). Phenol, 2,4-bis(1,1-dimethylethyl) of marine bacterial origin inhibits quorum sensing mediated biofilm formation in the uropathogen Serratia marcescens. Biofouling, 30(9), 1111–1122. https://doi.org/10.1080/08927014.2014.972386

    Article  PubMed  CAS  Google Scholar 

  26. Padmavathi, A. R., Periyasamy, M., & Pandian, S. K. (2015). Assessment of 2,4-di-tert-butylphenol induced modifications in extracellular polymeric substances of Serratia marcescens. Bioresource Technology, 188, 185–189. https://doi.org/10.1016/j.biortech.2015.01.049

    Article  PubMed  CAS  Google Scholar 

  27. Aissaoui, N., Mahjoubi, M., Nas, F., Mghirbi, O., Arab, M., Souissi, Y., Hoceini, A., Masmoudi, A. S., Mosbah, A., & Cherif, A. (2019). Antibacterial potential of 2, 4-di-tert-butylphenol and calixarene-based prodrugs from thermophilic Bacillus licheniformis isolated in Algerian hot spring. Geomicrobiology, 36, 53–62. https://doi.org/10.1080/01490451.2018.1503377

    Article  CAS  Google Scholar 

  28. Viszwapriya, D., Prithika, U., Deebika, S., Balamurugan, K., & Pandian, S. K. (2016). In vitro and in vivo antibiofilm potential of 2,4-di-tert-butylphenol from seaweed surface associated bacterium Bacillus subtilis against group A streptococcus. Microbiological Research, 191, 19–31. https://doi.org/10.1016/j.micres.2016.05.010

    Article  PubMed  CAS  Google Scholar 

  29. Leila, A., Lamjed, B., Roudaina, B., Najla, T., Taamalli, A., Jellouli, S., & Mokhtar, Z. (2019). Isolation of an antiviral compound from Tunisian olive twig cultivars. Microbial Pathogenesis, 128, 245–249. https://doi.org/10.1016/j.micpath.2019.01.012

    Article  PubMed  CAS  Google Scholar 

  30. Wayne, L. G., & Lin, K. Y. (1982). Glyoxylate metabolism and adaptation of Mycobacterium tuberculosis to survival under anaerobic conditions. Infection and Immunity, 37(3), 1042–1049. https://doi.org/10.1128/iai.37.3.1042-1049.1982

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wayne, L. G., & Hayes, L. G. (1996). An in vitro model for sequential study of shiftdown of Mycobacterium tuberculosis through two stages of nonreplicating persistence. Infection and Immunity, 64(6), 2062–2069. https://doi.org/10.1128/iai.64.6.2062-2069.1996

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Shleeva, M., Mukamolova, G. V., Young, M., Williams, H. D., & Kaprelyants, A. S. (2004). Formation of ‘non-culturable’ cells of Mycobacterium smegmatis in stationary phase in response to growth under suboptimal conditions and their Rpf-mediated resuscitation. Microbiology, 150, 1687–1697. https://doi.org/10.1099/mic.0.26893-0

    Article  PubMed  CAS  Google Scholar 

  33. Shleeva, M., Salina, E., & Kaprelyants, A. (2010). Dormant forms of mycobacteria. Microbiology, 79, 1–12. https://doi.org/10.1134/S0026261710010017

    Article  CAS  Google Scholar 

  34. Shleeva, M. O., Bagramyan, K., Telkov, M. V., Mukamolova, G. V., Young, M., Kell, D. B., & Kaprelyants, A. S. (2002). Formation and resuscitation of “non-culturable” cells of Rhodococcus rhodochrous and Mycobacterium tuberculosis in prolonged stationary phase. Microbiology, 148, 1581–1591. https://doi.org/10.1099/00221287-148-5-1581

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors acknowledge the management of Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India; Periyar University, Salem, Tamil Nadu, India; and CSIR-National Chemical Laboratory, Pune, India, for the research facilities provided.

Funding

The authors also thank the Department of Biotechnology (DBT) (BT/PR10814/AAQ/3/669/2014), New Delhi, India, for their support in the form of research grant.

Author information

Authors and Affiliations

  1. Centre for Drug Discovery and Development, Col. Dr. Jeppiaar Research Park, Sathyabama Institute of Science and Technology, Chennai, 600 119, Tamil Nadu, India

    Manigundan Kaari, Jerrine Joseph, Radhakrishnan Manikkam, Revathy Kalyanasundaram & Anbarasu Sivaraj

  2. Department of Microbiology, Periyar University, Salem, 636 011, Tamil Nadu, India

    Sivarajan Anbalmani, Sangeetha Murthy & Balagurunathan Ramasamy

  3. NCIM Resource Center, CSIR-National Chemical Laboratory, Pune, 411008, India

    Amit Kumar Sahu & Syed G. Dastager

  4. Academy of Scientific and Innovative Research (AcSIR), CSIR-National Chemical Laboratory, Pune, 411008, India

    Amit Kumar Sahu, Madhukar Said & Syed G. Dastager

  5. Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune, 411008, India

    Madhukar Said

Authors
  1. Manigundan Kaari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerrine Joseph
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Radhakrishnan Manikkam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Revathy Kalyanasundaram
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anbarasu Sivaraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sivarajan Anbalmani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sangeetha Murthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Amit Kumar Sahu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Madhukar Said
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Syed G. Dastager
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Balagurunathan Ramasamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MK, RK, SA, SM: performed the laboratory experiments; AKS, MS, SGD: performed purification and structural elucidation; MK, AS: analysis/interpretation of data; JJ, RM, BR: designed and supervising the work; MK, RK, AKS: drafting the manuscript; JJ, RM: critical revision of the manuscript.

Corresponding authors

Correspondence to Jerrine Joseph or Radhakrishnan Manikkam.

Ethics declarations

Ethical Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

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

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 4968 kb)

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

Kaari, M., Joseph, J., Manikkam, R. et al. A Novel Finding: 2,4-Di-tert-butylphenol from Streptomyces bacillaris ANS2 Effective Against Mycobacterium tuberculosis and Cancer Cell Lines. Appl Biochem Biotechnol 195, 6572–6585 (2023). https://doi.org/10.1007/s12010-023-04403-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-023-04403-2

Keywords

Search

Navigation