Streptococcus suis is an important swine pathogen associated with a variety of infections such as meningitis, arthritis and septicemia. The bacterium is zoonotic and has been found to cause meningitis especially in humans occupationally exposed to infected pigs. Since adhesion is a prerequisite for colonization and subsequent infection, anti-adhesion treatment seems a natural alternative to traditional treatment with antibiotics. In order to optimize the inhibitory potency a multivalency approach was taken in the inhibitor design. A synthetic tetravalent galabiose compound was chosen which had previously shown promising anti-adhesion effects with S. suis in vitro. The aim of this study was to evaluate the in vivo effects of the compound using an infection peritonitis mouse model. As such S. suis serotype 2 infection and treatment were tested in vivo and the effects were compared to the effect of treatment with penicillin.
References
[1]
Costa, A.T.R.; Lobato, F.C.F.; Abreu, V.L.V.; Assis, R.A.; Reis, R.; Uzal, F.A. Serotyping and evaluation of the virulence in mice of Streptococcus suis strains isolated from diseased pigs. Rev. Inst. Med. Trop. S Paulo 2005, 47, 113–115, doi:10.1590/S0036-46652005000200012.
[2]
Huang, Y.-T.; Teng, L.-J.; Ho, S.-W.; Hsueh, P.-R. Streptococcus suis Infection. J. Microbiol. Immunol. Infect. 2005, 38, 306–313.
[3]
Schultsz, C.; Jansen, E.; Keijzers, W.; Rothkamp, A.; Duim, B.; Wagenaar, J.A.; van der Ende, A. Differences in the Population Structure of Invasive Streptococcus suis Strains Isolated from Pigs and from Humans in the Netherlands. Plos. One 2012, 7, e33854.
[4]
Segura, M.; Gottschalk, M. Extracellular virulence factors of streptococci associated with animal disease. Front. Biosci. 2004, 9, 1157–1188, doi:10.2741/1287.
[5]
Madsen, L.W.; Aalb？k, B.; Nielsen, O.L.; Jensen, H.E. Aerogenous infection of microbiologically defined minipigs with Streptococcus suis serotype 2. APMIS 2001, 109, 412–418.
[6]
Seitz, M.; Beineke, A.; Seele, J.; Fulde, M.; Valentin-Weigand, P.; Baums, C.G. A novel intranasal mouse model for mucosal colonization by Streptococcus suis serotype 2. J. Med. Microbiol. 2012, 61, 1311–1318, doi:10.1099/jmm.0.043885-0.
[7]
Wisselink, H.J.; Smith, H.E.; Stockhofe-Zurwieden, N.; Peperkamp, K.; Vecht, U. Distribution of capsular types and production of muramidase-relesed protein (MRP) and extracellular factor (EF) of Streptococcus suis strains isolated from diseased pigs in seven European countries. Vet. Microbiol. 2000, 74, 237–248, doi:10.1016/S0378-1135(00)00188-7.
[8]
Pieters, R.J. Intervention with bacterial adhesion by multivalent carbohydrates. Med. Res. Rev. 2007, 27, 796–816, doi:10.1002/med.20089.
Kouki, A.; Haataja, S.; Loimaranta, V.; Pulliainen, A.T.; Nilsson, U.J.; Finne, J. Identification of a Novel Streptococcal Adhesin P (SadP) Protein Recognizing Galactosyl-alpha 1–4-galactose-containing Glycoconjugates convergent evolution of bacterial pathogens to binding of the same host receptor. J. Biol. Chem. 2011, 286, 38854–38864.
[11]
Tikkanen, K.; Haataja, S.; Finne, J. The Galactosyl-(α1–4)-Galactose-binding adhesin of Streptococcus suis: Occurrence in strains of different hemagglutination activity and induction of opsonic antibodies. Infect. Immun. 1996, 64, 3659–3665.
[12]
Ohlsson, J.; Larsson, A.; Haataja, S.; Alaj？？ski, J.; Stenlund, P.; Pinker, J.S.; Hultgren, S.J.; Finne, J.; Kihlberg, J.; Nilsson, U.J. Structure-activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins. Org. Biomol. Chem. 2005, 3, 886–900.
[13]
Haataja, S.; Zhang, Z.; Tikkanen, K.; Magnusson, G.; Finne, J. Determination of the cell adhesion specificity of Streptococcus suis with the complete set of monodeoxy analogues of globotriose. Glycoconjugate. J. 1999, 16, 67–71, doi:10.1023/A:1006905904544.
[14]
Kurl, D.N.; Haataja, S.; Finne, J. Hemagglutionation activities of group B, C, D and G Streptococci: Demonstration of novel sugar-specific cell-binding activities in Streptococcus suis. Infect. Immun. 1989, 57, 384–389.
[15]
Sperling, O.; Fuchs, A.; Lindhorst, T.K. Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH: design, synthesis and binding properties of mannoside ligands. Org. Biomol. Chem. 2006, 4, 3913–3922, doi:10.1039/b610745a.
[16]
Han, Z.; Pinkner, J.S.; Ford, B.; Chorell, E.; Crowley, J.M.; Cusumano, C.K.; Campbell, S.; Henderson, J.P.; Hultgren, S.J.; Janetka, J.W. Lead Optimization Studies on FimH Antagonists: Discovery of Potent and Orally Bioavailable Ortho-Substituted Biphenyl Mannosides. J. Med. Chem. 2012, 55, 3945–3959, doi:10.1021/jm300165m.
Almant, M.; Moreau, V.; Kovensky, J.; Bouckaert, J.; Gouin, S.G. Clustering of Escherichia coli Type-1 Fimbrial Adhesins by Using Multimeric Heptyl alpha-D-Mannoside Probes with a Carbohydrate Core. Chem. Eur. J. 2011, 17, 10029–10038.
[19]
Salminen, A.; Loimaranta, V.; Joosten, J.A. F.; Khan, A.S.; Hacker, J.; Pieters, R.J.; Finne, J. Inhibition of P-fimbriated Escherichia coli adhesion by multivalent galabiose derivatives studied by a live-bacteria application of surface plasmon resonance. J. Antimicrob. Chemother. 2007, 60, 495–501, doi:10.1093/jac/dkm251.
[20]
oosten, J.F.; Loimaranta, V.; Appeldoorn, C.C.; Haataja, S.; Ait El Maate, F.; Liskamp, R.M.J.; Finne, J.; Pieters R, J. Inhibition of Streptococcus suis adhesion by dendritic galabiose compounds at low nanomolar concentration. J. Med. Chem. 2004, 26, 6499–6508.
[21]
Hansen, H.C.; Haataja, S.; Finne, J.; Magnusson, G. Di-, tri-, and tetravalent dendritic galabiosides that inhibit hemagglutination by Streptococcus suis at nanomolar concentration. J. Am. Chem. Soc. 1997, 119, 6974–6979, doi:10.1021/ja970859p.
[22]
Branderhorst, H.M.; Kooij, R.; Salminen, A.; Jongeneel, L.H.; Arnusch, C.J.; Liskamp, R.M. J.; Finne, J.; Pieters, R.J. Synthesis of multivalent Streptococcus suis adhesion inhibitors by enzymatic cleavage of polygalacturonic acid and 'click' conjugation. Org. Biomol. Chem. 2008, 6, 1425–1434, doi:10.1039/b800283e.
[23]
Pera, N.P.; Kouki, A.; Haataja, S.; Branderhorst, H.M.; Liskamp, R.M. J.; Visser, G.M.; Finne, J.; Pieters, R.J. Detection of pathogenic Streptococcus suis bacteria using magnetic glycoparticles. Org. Biomol. Chem. 2010, 8, 2425–2429, doi:10.1039/c000819b.
[24]
Nishikawa, K.; Matsuoka, K.; Kita, E.; Okabe, N.; Mizuguchi, M.; Hino, K.; Miyazawa, S.; Yamasaki, C.; Aoki, J.; Takashima, S.; Yamakawa, Y.; Nishijima, M.; Terunuma, D.; Kuzuhara, H.; Natori, Y. A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157: H7. Proc. Natl. Acad. Sci. USA 2002, 99, 7669–7674, doi:10.1073/pnas.112058999.
[25]
Dominguez-Punaro, M.C.; Koedel, U.; Hoegen, T.; Demel, C.; Klein, M.; Gottschalk, M. Severe cochlear inflammation and vestibular syndrome in an experimental model of Streptococcus suis infection in mice. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 2391–2400, doi:10.1007/s10096-012-1581-2.
[26]
Williams, A.E.; Blakemore, W.F.; Alexander, T.J.L. A murine model of Streptococcus suis type 2 meningitis in the pig. Res. Vet. Sci. 1988, 45, 394–399.
[27]
Beaudoin, M.; Higgins, R.; Harel, J.; Gottschalk, M. Studies on a murine model for evaluation of virulence of Streptococcus suis capsular type 2 isolates. Fems. Microbiol. Lett. 1992, 99, 111–116, doi:10.1111/j.1574-6968.1992.tb05552.x.
[28]
Kataoka, Y.; Haritani, M.; Mori, M.; Kishima, M.; Sugimoto, C.; Nakazawa, M.; Yamamoto, K. Experimental infections of mice and pigs with Streptococcus suis type 2. J. Vet. Med. Sci. 1991, 53, 1043–1049, doi:10.1292/jvms.53.1043.
[29]
Robertson, I.D.; Blackmore, D.K. Experimental studies on the comparative infectivity and pathogenicity of Streptococcus suis type 2. II. Porcine and human isolates in laboratory animals. Epidemiol. Infect. 1990, 105, 479–484, doi:10.1017/S0950268800048093.
[30]
Slotved, H-C.; Sauer, S.; Konradsen, H.B. False-negative results in typing of group B streptococci by the standard Lancefield antigen extraction method. J. Clin. Microbiol. 2002, 40, 1882–1883, doi:10.1128/JCM.40.5.1882-1883.2002.
[31]
Vecht, U.; Stockhofe-Zurwieden, N.; Tetenburg, B.J.; Wisselink, H.J.; Smith, H.E. Virulence of Streptococcus suis type 2 for mice and pigs appeared host-specific. Vet. Microbiol. 1997, 58, 53–60, doi:10.1016/S0378-1135(97)00131-4.
[32]
Segura, M.; Gottschalk, M. Streptococcus suis interactions with the murine macrophage cell line J774: Adhesion and cytotoxicity. Infect. Immun. 2002, 70, 4312–4322, doi:10.1128/IAI.70.8.4312-4322.2002.
[33]
Benga, L.; Friedl, P.; Valentin-Weigand, P. Adherence of Streptococcus suis to Porcine Endothelial Cells. J. Vet. Med. 2005, B52, 392–395.
[34]
Vanier, G.; Segura, M.; Friedl, P.; Lacouture, S.; Gottschalk, M. Invasion of porcine brain microvascular endothelial cells by Streptococcus suis serotype 2. Infect. Immun. 2004, 72, 1441–1449, doi:10.1128/IAI.72.3.1441-1449.2004.
[35]
Lalonde, M.; Segura, M.; Lacouture, S.; Gottschalk, M. Interactions between Streptococcus suis serotype 2 and different epithelial cell lines. Microbiology 2000, 146, 1913–1921.
[36]
Gottschalk, M.; Segura, M. The pathogenesis of the meningitis caused by Streptococcus suis: the unresolved questions. Vet. Microbiol. 2000, 76, 259–272, doi:10.1016/S0378-1135(00)00250-9.
[37]
Staats, J.J.; Feder, I.; Okwumabua, O.; Chengappa, M.M. Streptococcus: Past and present. Vet. Res. Commun. 1997, 21, 381–407, doi:10.1023/A:1005870317757.
[38]
Haataja, S.; Tikkanen, K.; Hytonen, J.; Finne, J. The Gal alpha 1–4 Gal-binding adhesin of Streptococcus suis, a gram-positive meningitis-associated bacterium. Adv. Exp. Med. Biol. 1996, 408, 25–34.
