Skip to main content
SpringerLink
Log in

Activity and Synergistic Antimicrobial Activity Between Diketopiperazines Against Bacteria In Vitro

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

Abstract

The aim of the present study was to determine the synergistic effects of diketopiperazines [cyclo-(l-Pro-l-Leu) (1), cyclo-(d-Pro-l-Leu) (2), and cyclo-(d-Pro-l-Tyr) (3)] purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp. on the growth of bacteria. The minimum inhibitory concentration and minimum bactericidal concentration of the diketopiperazines was compared with that of the standard antibiotics. The synergistic antibacterial activities of the combination of diketopiperazines against pathogenic bacteria were assessed using the checkerboard assay and time–kill methods. The results of the present study showed that the combination effects of diketopiperazines were predominately synergistic (FIC index <0.5). Furthermore, time–kill study showed that the growth of the tested bacteria was completely attenuated with 4–12 h of treatment with 50:50 ratios of diketopiperazines. These results suggest that the combination of diketopiperazines may be microbiologically beneficial. The three diketopiperazines are nontoxic to normal human cell line (L231 lung epithelial) up to 200 m μg/ml. The in vitro synergistic activity of cyclo-(l-Pro-l-Leu), cyclo-(d-Pro-l-Leu), and cyclo-(d-Pro-l-Tyr) against bacteria is reported here for the first time. These findings have potential implications in delaying the development of resistance as the antibacterial effect is achieved with lower concentrations of both drugs (diketopiperazines).

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

References

  1. Chung, P. Y., Navaratnam, P., & Chung, L. Y. (2011). Annals of Clinical Microbiology and Antimicrobials, 10, 25.

    Article  CAS  Google Scholar 

  2. Levy, S. B. (2002). The antibiotic paradox: how misuse of antibiotics destroys their curative powers (2nd ed.). Boston: Perseus.

    Google Scholar 

  3. Stuart, B. L., & Marshall, B. (2005). Nature Medicine, 10, 122–129.

    Google Scholar 

  4. Austin, D. J., Kristinsson, K. G., & Anderson, R. M. (1999). Proceedings of the National Academy of Science, 96, 1152–1156.

    Article  CAS  Google Scholar 

  5. Guillemot, D. (1999). Current Opinion in Microbiology, 2, 494–498.

    Article  CAS  Google Scholar 

  6. Beringer, P. M. (1999). Current Opinion in Pulmonary Medicine, 5, 371–377.

    Article  CAS  Google Scholar 

  7. Sweeney, M. T., & Zurenko, G. E. (2003). Antimicrobial Agents and Chemotherapy, 47(6), 1902–1906.

    Article  CAS  Google Scholar 

  8. Marokhazi, J., Lengyel, K., Pekar, S., Felfoldi, G., Patthy, A., Graf, L., et al. (2004). Applied and Environmental Microbiology, 70, 7311–7320.

    Article  CAS  Google Scholar 

  9. Paul, V. J., Frautschy, S., Fenical, W., & Nealson, K. H. (1981). Journal of Chemical Ecology, 7, 589–597.

    Article  CAS  Google Scholar 

  10. McInerney, B. V., Gregson, R. P., Lacey, M. J., Akhurst, R. J., Lyons, G. R., Rhodes, S. H., et al. (1991). Journal of Natural Products, 54, 774–784.

    Article  CAS  Google Scholar 

  11. McInerney, B. V., Taylor, W. C., Lacey, M. J., Akhurst, R. J., & Gregson, R. P. (1991). Journal of Natural Products, 54, 785–795.

    Article  CAS  Google Scholar 

  12. Li, J. X., Chen, G. H., & Webster, J. M. (1997). Canadian Journal of Microbiology, 43, 770–773.

    Article  CAS  Google Scholar 

  13. Ji, D. J., Yi, Y. K., & Kang, G. H. (2004). FEMS Microbiology Letters, 239, 241–248.

    Article  CAS  Google Scholar 

  14. Lang, G., Kalvelage, T., Peters, A., Wiese, J., & Imhoff, J. F. (2008). Journal of Natural Products, 71, 1074–1077.

    Article  CAS  Google Scholar 

  15. Gualtieri, M., Aumelasm, A., & Thaler, J. O. (2009). Journal of Antibiotics, 62, 295–302.

    Article  CAS  Google Scholar 

  16. Kumar, N. S., Mohandas, C., Siji, J. V., Rajasekharan, K. N., & Nambisan, B. (2012). Journal of Applied Microbiology. doi:10.1111/j.1365-2672.2012.05385.x.

  17. Prasad, C. (1995). Peptides, 16, 151–164.

    Article  CAS  Google Scholar 

  18. Rudi, A., Kashman, Y., Benayahu, Y., & Schleyer, M. (1994). Journal of Natural Products, 5, 829–832.

    Article  Google Scholar 

  19. Strom, K., Sjogren, J., Broberg, A., & Schnurer, J. (2002). Applied and Environmental Microbiology, 68, 4322–4327.

    Article  CAS  Google Scholar 

  20. Rosa, S. D., Mitova, M., & Tommonaro, G. (2003). Biomolecular Engineering, 20, 311–316.

    Article  Google Scholar 

  21. Nicholson, B., Lloyd, G. K., Miller, B. R., Palladino, M. A., Kiso, Y., Hayashi, Y., et al. (2006). Anti-Cancer Drugs, 17, 25–31.

    Article  CAS  Google Scholar 

  22. van der Merwe, E., Huang, D., Peterson, D., Kilian, G., Milne, P. J., Van de Venter, M., et al. (2008). Peptides, 29, 1305–1311.

    Article  Google Scholar 

  23. Houston, D. R., Synstad, B., Eijsink, V. G., Stark, M. J., Eggleston, I. M., & van Aalten, D. M. (2004). Journal of Medicinal Chemistry, 47, 5713–5720.

    Article  CAS  Google Scholar 

  24. Fdhila, F., Vazquez, V., Sanchez, J. L., & Riguera, R. (2003). Journal of Natural Products, 66, 1299–1301.

    Article  CAS  Google Scholar 

  25. CLSI, Clinical and Laboratory Standards Institute. (2006). CLSI documents M27-S3. 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA

  26. Pillai, S.K. & Moellering, R.C. (2005). (pp. 365–400) New York: Lippincott Williams & Wilkins.

  27. Yu, H. H., Kim, K. J., Cha, J. D., Kim, H. K., Lee, Y. E., Choi, N. Y., et al. (2005). Journal of Medicinal Food, 8, 454–461.

    Article  CAS  Google Scholar 

  28. Lee, Y., Jang, K., & Cha, J. (2012). Journal of Biomedicine and Biotechnology. doi:10.1155/2012/618081:1-7.

  29. NCCLS, National Committee for Clinical Laboratory Standards. (1999). M26-A (Vol. 19). Wayne: National Committee for Clinical Laboratory Standards.

    Google Scholar 

  30. Anto, R. J., Venkataraman, M., & Karunagaran, D. (2003). Journal of Biological Chemistry, 28, 25490–25498.

    Article  Google Scholar 

  31. Grey, D., Hamilton-Miller, J. M., & Brumfitt, W. (1979). Chemotherapy, 25, 296–302.

    Article  CAS  Google Scholar 

  32. King, T. C., Schlessinger, D., & Krogstad, D. J. (1981). Reviews of Infectious Diseases, 3, 627–633.

    Article  CAS  Google Scholar 

  33. Niku-Paavola, M. L., Laitila, A., Mattila-Sandholm, T., & Haikara, A. (1999). Journal of Applied Microbiology, 87, 29–35.

    Article  Google Scholar 

  34. Lambert, R. J., Johnston, M. D., Hanlon, G. W., & Denyer, S. P. (2003). Journal of Applied Microbiology, 94, 747–759.

    Article  CAS  Google Scholar 

  35. Matsushima, M., Sugimura, T., Nagao, T., Shirai, A. & Sawamur, M. (1980). (pp. 273–285). Berlin: Springer

  36. Graz, M., Hunt, A., Jamie, H., Grant, G., & Milne, P. (1999). Pharmazie, 54, 772–775.

    CAS  Google Scholar 

  37. Holden, M. T. G., Chhabra, S. R., de Nys, R., Stead, P., Bainton, N. J., Hill, P. J., et al. (1999). Molecular Microbiology, 33, 1254–1266.

    Article  CAS  Google Scholar 

  38. Katrin, S., Jorgen, S., Anders, B., & John, S. (2002). Applied and Environmental Microbiology, 68, 4322–4327.

    Article  Google Scholar 

  39. Rhee, K. H. (2004). International Journal of Antimicrobial Agents, 24, 423–427.

    Article  CAS  Google Scholar 

  40. Milne, P. J., Hunt, A. L., Rostoll, K., Vanderwalt, J. J., & Graz, C. J. M. (1998). Journal of Pharmacy and Pharmacology, 50, 1331–1337.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Indian Council Medical Research, Government of India for funding. We thank the director, CTCRI, for providing facilities for the work.

Author information

Authors and Affiliations

  1. Division of Crop Protection/Division of Crop Utilization, Central Tuber Crops Research Institute, Sreekariyam, Thiruvananthapuram, 695017, India

    S. Nishanth Kumar, J. V. Siji, Bala Nambisan & C. Mohandas

  2. SRF Division of Crop Protection, Central Tuber Crops Research Institute, Sreekariyam, Thiruvananthapuram, 695017, India

    S. Nishanth Kumar

Authors
  1. S. Nishanth Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. V. Siji
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bala Nambisan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Mohandas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Nishanth Kumar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kumar, S.N., Siji, J.V., Nambisan, B. et al. Activity and Synergistic Antimicrobial Activity Between Diketopiperazines Against Bacteria In Vitro. Appl Biochem Biotechnol 168, 2285–2296 (2012). https://doi.org/10.1007/s12010-012-9937-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12010-012-9937-8

Keywords

Search

Navigation