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Cyclic dipeptides from lactic acid bacteria inhibit proliferation of the influenza a virus

Abstract

We isolated Lactobacillus plantarum LBP-K10 from the traditional Korean fermented food kimchi. When organic acids were removed, the culture filtrate of this isolate showed high antiviral activity (measured using a plaque-forming assay) against the influenza A (H3N2) virus. Two fractions that were active against influenza A virus were purified from the culture filtrate using a C18 column with high-performance liquid chromatography. These active fractions were crystallized and identified to be the cyclic dipeptides cis-cyclo (l-Leu-l-Pro) and cis-cyclo(l-Phe-l-Pro) using gas chromatography-mass spectrometry; this identification was confirmed by X-ray crystallography. These cyclic dipeptides were identified in the culture filtrate of other lactic acid bacteria, including Lactobacillus spp., Leuconostoc spp., Weissella spp., and Lactococcus lactis.

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References

  • Alak, J.I., Wolf, B.W., Mdurvwa, E.G., Pimentel-Smith, G.E., and Adeyemo, O. 1997. Effect of Lactobacillus reuteri on intestinal resistance of Cryptosporidium parvum infection in a murine model of acquired immuno-deficiency syndrome. J. Infect. Dis. 175, 218–221.

    CAS  PubMed  Article  Google Scholar 

  • Borthwick, A.D. 2012. 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 112, 3641–3716.

    CAS  PubMed  Article  Google Scholar 

  • De Man, J.C., Rogosa, M., and Sharpe, M.E. 1960. A medium for the cultivation of Lactobacilli. J. Appl. Microbiol. 23, 130–135.

    Google Scholar 

  • Digaitiene, A., Hansen, Josephsen, J. 2012. Lactic acid bacteria isolated from rye sourdoughs produce bacteriocin-like inhibitory substances active against Bacillus subtilis and fungi. J. Appl. Microbiol. 112, 732–742.

    CAS  PubMed  Article  Google Scholar 

  • Ducluzeau, R., Dubos, F., and Raibaud, P. 1971. Antagonist effect of a Lactobacillus strain on a Ristella sp. strain in the digestive tract of gnotoxenic mice ingesting lactose. Ann. Inst. Pasteur. (Paris) 121, 777–794.

    CAS  Google Scholar 

  • Gänzle, M.G., Höltzel, A., Walter, J., Jung, G., and Hammes, W.P. 2000. Characterization of reutericyclin produced by Lactobacillus reuteri LTH2584. Appl. Environ. Microbiol. 66, 4325–4333.

    PubMed Central  PubMed  Article  Google Scholar 

  • Gao, Q., Liu, F., Zhang, T., Zhang, J., Jia, S., Yu, C., Jiang, K., and Gao, N. 2010. The role of lactic acid adsorption by ion exchange chromatography. PLoS One 5, e13948.

    PubMed Central  PubMed  Article  Google Scholar 

  • Graz, M., Hunt, A., Jamie, H., Grant, G., and Milne, P. 1999. Antimicrobial activity of selected cyclic dipeptides. Pharmazie 54, 772–775.

    CAS  PubMed  Google Scholar 

  • Huprikar, J. and Rabinowitz, S. 1980. A simplified plaque assay for influenza viruses in Madin-Darby kidney (MDCK) cells. J. Virol. Methods 1, 117–120.

    CAS  PubMed  Article  Google Scholar 

  • Jefferies, W.M., Turner, J.C., Lobo, M., and Gwaltney, J.M. Jr. 1998. Low plasma levels of adrenocorticotropic hormone in patients with acute influenza. Clin. Infect. Dis. 26, 708–710.

    CAS  PubMed  Article  Google Scholar 

  • Kanzaki, H., Imura, D., Nitoda, T., and Kawazu, K. 2000. Enzymatic conversion of cyclic dipeptides to dehydro derivatives that inhibit cell division. J. Biosci. Bioeng. 90, 86–89.

    CAS  PubMed  Google Scholar 

  • Lee, K.H., Kim, K.W., and Rhee, K.H. 2010. Identification of Streptomyces sp. KH29, which produces an antibiotic substance processing an inhibitory activity against multidrug-resistant Acinetobacter baumannii. J. Microbiol. Biotechnol. 20, 1672–1676.

    CAS  PubMed  Google Scholar 

  • Li, H., Liu, L., Zhang, S., Cui, W., and Lv, J. 2012. Identification of antifungal compounds produced by Lactobacillus casei AST18. Curr. Microbiol. 65, 156–161.

    CAS  PubMed  Article  Google Scholar 

  • Li, J., Wang, W., Xu, S.X., Magarvey, N.A., and McCormick, J.K. 2011. Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proc. Natl. Acad. Sci. USA 108, 3360–3365.

    CAS  PubMed  Article  Google Scholar 

  • Li, X., Hopmann, K.H., Hudecová, J., Isaksson, J., Novotná, J., Stensen, W., Andrushchenko, V., Urbanová, M., Svendsen, J.S., Bouř, P., and et al. 2013. Determination of absolute configuration and conformation of a cyclic dipeptide by NMR and chiral spectroscopic methods. J. Phys. Chem. A. 117, 1721–1736.

    CAS  PubMed  Article  Google Scholar 

  • Magnusson, J., Ström, K., Roos, S., Sjögren, J., and Schnürer, J. 2003. Broad and complex antifungal activity among environmental isolates of lactic acid bacteria. FEMS Microbiol. Lett. 219, 129–135.

    CAS  PubMed  Article  Google Scholar 

  • Matsuda, T. 1994. Antimicrobial activities of organic acids determined by minimum inhibitory concentrations at different PH ranged from 4.0 to 7.0. Nippon Shokuhin Kogyo Gakkaishi 41, 687–702.

    CAS  Article  Google Scholar 

  • McCleland, K., Milne, P.J., Lucieto, F.R., Frost, C., Brauns, S.C., Van De Venter, M., Du Plessis, J., and Dyason, K. 2004. An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr). J. Pharm. Pharmacol. 56, 1143–1153.

    CAS  PubMed  Article  Google Scholar 

  • Mezaini, A., Chihib, N.E., Bouras, A.D., Nedjar-Arroume, N., and Hornez, J.P. 2009. Antibacterial activity of some lactic acid bacteria isolated from an Algerian dairy product. J. Environ. Public Health 2009, 1–6.

    Article  Google Scholar 

  • Naidu, A.S., Bidlack, W.R., and Clemens, R.A. 1999. Probiotic spectra of lactic acid bacteria (LAB). Crit. Rev. Food Sci. Nutr. 39, 13–126.

    CAS  PubMed  Article  Google Scholar 

  • Niku-Paavola, M.L., Laitila, A., Mattila-Sandholm, T., and Haikara, A. 1999. New types of antimicrobial compounds produced by Lactobacillus plantarum. J. Appl. Microbiol. 86, 29–35.

    CAS  PubMed  Article  Google Scholar 

  • Prasad, C. 1995. Bioactive cyclic dipeptides. Peptides 16, 151–164.

    CAS  PubMed  Article  Google Scholar 

  • Rani, B. and Khetarpaul, N. 1998. Probiotic fermented food mixtures: possible applications in clinical anti-diarrhoea usage. Nutr. Hlth. 12, 97–105.

    CAS  Google Scholar 

  • Rhee, K.H. 2004. Cyclic dipeptides exhibit synergistic, broad spectrum antimicrobial effects and have anti-mutagenic properties. Int. J. Antimicrob. Agents 24, 423–427.

    CAS  PubMed  Article  Google Scholar 

  • Ross, R.P., Morgan, S., and Hill, C. 2002. Preservation and fermentation: past, present and future. Int. J. Food Microbiol. 79, 3–16.

    CAS  PubMed  Article  Google Scholar 

  • Rouse, S. and van Sinderen, D. 2008. Bioprotective potential of lactic acid bacteria in malting and brewing. J. Food Prot. 71, 1724–1733.

    PubMed  Google Scholar 

  • Savage, D.C. 1969. Microbial interference between indigenous yeast and lactobacilli in the rodent stomach. J. Bacteriol. 98, 1278–1283.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Steinhauer, D.A. 1999. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258, 1–20.

    CAS  PubMed  Article  Google Scholar 

  • Ström, K., Sjögren, J., Broberg, A., and Schnürer, J. 2002. Lactobacillus plantarum MiLAB 393 produces the antifungal cyclic dipeptides cyclo(l-Phe-l-Pro) and cyclo(l-Phe-trans-4-OH-l-Pro) and 3-phenyllactic acid. Appl. Environ. Microbiol. 68, 4322–4327.

    PubMed Central  PubMed  Article  Google Scholar 

  • Trabocchi, A., Scarpi, D., and Guarna, A. 2008. Structural diversity of bicyclic amino acids. Amino Acids 34, 1–24.

    CAS  PubMed  Article  Google Scholar 

  • Tsuruoka, N., Beppu, Y., Koda, H., Doe, N., Watanabe, H., and Abe, K. 2012. A DKP cyclo(L-Phe-L-Phe) found in chicken essence is a dual inhibitor of the serotonin transporter and acetylcholine sterase. PLoS One 7, e50824.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  • Van der Merwe, E., Huang, D., Peterson, D., Kilian, G., Milne, P.J., Van de Venter, M., and Frost, C. 2008. The synthesis and anticancer activity of selected diketopiperazines. Peptides 29, 1305–1311.

    PubMed  Article  Google Scholar 

  • Wagner, R.D., Pierson, C., Warner, T., Dohnalek, M., Farmer, J., Roberts, L., Hilty, M., and Balish, E. 1997. Biotherapeutic effects of probiotic bacteria on candidiasis in immunodeficient mice. Infect. Immun. 65, 4165–4172.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Watanabe, W., Konno, K., Ijichi, K., Inoue, H., Yokota, T., and Shigeta, S. 1994. MTT colorimetric assay system for the screening of anti-orthomyxo- and anti-paramyxoviral agents. J. Virol. Methods 48, 257–265.

    CAS  PubMed  Article  Google Scholar 

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Correspondence to Sa-Ouk Kang.

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Kwak, MK., Liu, R., Kwon, JO. et al. Cyclic dipeptides from lactic acid bacteria inhibit proliferation of the influenza a virus. J Microbiol. 51, 836–843 (2013). https://doi.org/10.1007/s12275-013-3521-y

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  • DOI: https://doi.org/10.1007/s12275-013-3521-y

Keywords

  • Lactobacillus plantarum LBP-K10
  • culture filtrate
  • cis-cyclo(l-Leu-l-Pro)
  • cis-cyclo(l-Phe-l-Pro)
  • influenza A virus
  • antiviral activity