Fachbereich Veterinärmedizin



    More complicated than imagined:
    What mechanisms lead to benzimidazole resistance in helminths? (2017)

    von Samson-Himmelstjerna, Georg (WE 13)
    Krücken, Jürgen (WE 13)
    18th Drug Design & Development Seminar (DDDS) of the German Seciety for Parasitology (DGP)
    Borstel, Germany, 30. – 31.03.2017
    18th Drug Design & Development Seminar (DDDS) of the German Society for Parasitology (DGP) March 30th – 31st, 2017
    Borstel, 2017 — S. 12
    URL (Volltext): http://www.helminguard.de/fix/files/301/doc/18th%20DDDS%20conference%20brochure.pdf
    Institut für Parasitologie und Tropenveterinärmedizin

    Robert-von-Ostertag-Str. 7-13
    Gebäude 35, 22, 23
    14163 Berlin
    +49 30 838 62310

    Abstract / Zusammenfassung

    Only since the start of the area of broad spectrum anthelmintics in the 1960s safe, affordable and effective treatment and control of helminth infections has become available. As the first real broad spectrum antiparasiticides, the benzimidazoles (BZ) are in use against gastro-intestinal nematodes (GIN) as well as some cestode and even protozoan parasite species for now more than five decades. The frequent and intensive use of anthelmintics can lead to drug resistance as also known for other antiinfectives. For the BZs this has already been reported during the early 1970s in small ruminant GIN and since then became a widespread problem in this important group of parasites as well as in equine cyathostomins. More recently, BZ resistance has been seen also in cattle GIN [1] and our own recent investigations indicate also a sub optimal response of Ascaris sp. in African school children. BZs act by binding with high affinity to the β-tubulins of pathogens which leads to a blocking of microtubule polymerization and due to the ongoing depolymerization thus subsequently to a complete loss of these essential cell structure. By comparison of the β-tubulin isotype 1 coding sequences from BZ-susceptible and –resistant populations of the sheep GIN Haemonchus contortus it was found that a single nucleotide polymorphism at the codon 200 leading to the expression of tyrosine instead of phenylalanine correlates with BZ resistance. Subsequently the similar P167Y and an E198A polymorphism were also described to be associated with BZ-resistance in this and other GIN species. In addition to these drug target related BZ resistance mechanisms, subsequently also unspecific resistance mechanisms involving an increased drug efflux mediated by P-glycoprotein transmembrane pumps were encountered. However, it is currently unclear which of the many P-glycoprotein genes of parasitic nematodes are involved in this process. Furthermore, also the modification of cytochrome P450 based drug metabolism was recently suggested to potentially be associated with BZ resistance in nematodes [2]. Noteworthy, parasite species and even population specific differences concerning the relevance of the various potential BZ resistance mechanisms have already been demonstrated. Future research should address the question if certain selectional factors contribute to the evolution of specific resistance mechanism, which fitness costs (if any) are associated with the different resistance mechanisms and if for example combinations of resistance mechanisms also occur.