Intern
    Institut für Hygiene und Mikrobiologie

    Drug development

    Current chemotherapeutic options for the treatment of alveolar echinococcosis are very limited. Routinely, benzimidazoles are used which target the parasite’s beta-tubulins (85% identical to mammalian beta-tubulin; Brehm et al., 1999) and which can have severe side-effects. Furthermore, benzimidazoles are parasitostatic only and often have to be given life-long (Brehm, 2013).
    Due to the available molecular information and their crucial role in parasite development, the Echinococcus signalling cascades (see host-parasite interaction) are also suitable targets for anti-parasitic chemotherapy. The level of conservation of these factors is usually lower than that of beta-tubulins. Furthermore, due to cancer research many inhibitors and modifiers of the activity of these factors are available. In this project, we are testing commercially available anti-cancer drugs (e.g. kinase inhibitors) for antiparasitic activity (in vitro cultivation system) and for direct activity towards parasite targets (e.g. p38 MAP kinases or Abl-like kinases). Once such inhibitors are identified, they will be chemically modified to generate parasite-specific drugs.

    Detrimental effects of the anti-cancer drug Imatinib on Echinococcus larvae (Hemer and Brehm, 2012).

    References:

    Brehm, K., 2013 Protein kinases as drug targets in the treatment of alveolar echinococcosis.
    In Protein phosphorylation in eukaryotic parasites: novel targets for antiparasitic intervention. Drug discovery in infectious diseases (vol. 5). Edited by Doerig, C., Wiese, M., Spaeth, G. Wiley-VCH 2013; in press.

    Hemer, S., Brehm, K., 2012 In vitro efficacy of the anti-cancer drug Imatinib on Echinococcus multilocularis larvae.
    Int. J. Antimicrob. Agents 40: 458-462.

    Gelmedin, V., Spiliotis, M. & Brehm, K., 2010 Molecular Characterization of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox-tapeworm Echinococcus multilocularis.
    Int. J.Parasitol. 40: 555-567.

    Gelmedin, V., Caballero-Gamiz, R. & Brehm, K., 2008. Characterization and inhibition of a p38-like mitogen activated protein kinase (MAPK) from Echinococcus multilocularis: antiparasitic activities of p38 MAPK inhibitors.
    Biochem. Pharmacol. 76: 1068-1081.

    Spiliotis, M., Konrad, C., Gelmedin, V., Tappe, D., Brückner, S., Mösch, H.U. & Brehm, K., 2006 Characterisation of EmMPK1, an ERK-like MAP kinase from Echinococcus multilocularis which is activated in response to human epidermal growth factor.
    Int. J. Parasitol., 36: 1079-1112.

    Brehm, K., Kronthaler, K., Jura, H. & Frosch, M., 2000 Cloning and characterization of ß-tubulin genes from Echinococcus multilocularis. Mol. Biochem. Parasitol. 107: 297-302

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