Searching new targets for anthelminthic strategies: Interference with glycosphingolipid biosynthesis and phosphorylcholine metabolism affects development of Caenorhabditis elegans.
Nematode infections are amongst the most abundant diseases of man and animals. They are characterised by a low mortality but high morbidity, thus reflecting the adaptation of these parasites to their hosts. Resistance as well as severe side-effects and efficacies restricted to distinct larval stages or parasites of the anthelmithics used at present require the urgent development of new and more nematode-specific drugs, targeting enzymes of parasite restricted biosynthetic routes. Caenorhabditis elegans has been found to be a good model system for parasitic nematodes, drug screening and developmental studies. Structural analyses have revealed nematode-specific glycosphingolipid structures of the arthro-series, carrying in part, phosphorylcholine substituents. These biomolecules appear to play important roles in nematode development, fertility and survival within the host and are, therefore, good target-candidates for the development of new anthelminthic strategies. Here we show that RNAi experiments targeting enzymes of glycosphingolipid biosynthesis or choline metabolism result, in part, in a drastic reduction of fertility. We further tested various chemical inhibitors of these pathways and found significant effects on the development of the worms, resulting in developmental arrest, sterility and, in part, lethality. Such inhibitors can, therefore, help to define new classes of anthelminthics.
Lochnit
Günter
G
Faculty of Medicine, Institute of Biochemistry, University of Giessen, Friedrichstrasse 24, D-35392 Giessen, Germany. guenter.lochnit@biochemie.med.uni-giessen.de
Bongaarts
Rico
R
Geyer
Rudolf
R
D000818:Animals; D000871:Anthelmintics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000196:embryology / Q000201:enzymology / Q000254:growth & development*; D005298:Fertility / Q000502:physiology; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007814:Larva / Q000254:growth & development / Q000378:metabolism; D023421:Models, Animal; D010641:Phenotype; D010767:Phosphorylcholine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018510:RNA, Helminth / Q000378:metabolism; D013997:Time Factors
D000871:Anthelmintics; D006028:Glycosphingolipids; D018510:RNA, Helminth; D010767:Phosphorylcholine