Abstract
Intestinal cestodes are infecting millions of people and livestock worldwide, but treatment is mainly based on one drug: praziquantel. The identification of new anti-cestodal compounds is hampered by the lack of suitable screening assays. It is difficult, or even impossible, to evaluate drugs against adult cestodes in vitro due to the fact that these parasites cannot be cultured in microwell plates, and adult and larval stages in most cases represent different organisms in terms of size, morphology, and metabolic requirements. We here present an in vitro-drug screening assay based on Echinococcus multilocularis protoscoleces, which represent precursors of the scolex (hence the anterior part) of the adult tapeworm. This movement-based assay can serve as a model for an adult cestode screen. Protoscoleces are produced in large numbers in Mongolian gerbils and mice, their movement is measured and quantified by image analysis, and active compounds are directly assessed in terms of morphological effects. The use of the 384-well format minimizes the amount of parasites and compounds needed and allows rapid screening of a large number of chemicals. Standard drugs showed the expected dose-dependent effect on movement and morphology of the protoscoleces. Interestingly, praziquantel inhibited movement only partially within 12 h of treatment (at concentrations as high as 100 ppm) and did thus not act parasiticidal, which was also confirmed by trypan blue staining. Enantiomers of praziquantel showed a clear difference in their minimal inhibitory concentration in the motility assay and (R)-(-)-praziquantel was 185 times more active than (S)-(-)-praziquantel. One compound named MMV665807, which was obtained from the open access MMV (Medicines for Malaria Venture) Malaria box, strongly impaired motility and viability of protoscoleces. Corresponding morphological alterations were visualized by scanning electron microscopy, and demonstrated that this compound exhibits a mode of action clearly distinct from praziquantel. Thus, MMV665807 represents an interesting lead for further evaluation.
Highlights
Helminths are separated into the two major phyla of nematodes and platyhelminths, including trematodes and cestodes, and they are important causes of disease in humans as well as animals
The clinical signs caused by intestinal infection with adult cestodes are mostly mild, in contrast to the more severe disease symptoms inflicted by infection with the tissue-dwelling larval stages of the same species
Praziquantel is the main drug in use against intestinal cestode infections
Summary
Helminths are separated into the two major phyla of nematodes (roundworms) and platyhelminths (flatworms), including trematodes and cestodes, and they are important causes of disease in humans as well as animals. Despite the large number of infected individuals and enormous economic losses due to helminth infections in animals, there are still not many drugs registered for their treatment [1]. Most of the adult stages of trematodes, and all cestodes, are not being considered in the current drug screening efforts. Intestinal cestodes might be considered as parasites of lower relevance as they usually cause few clinical signs, but they are of high relevance as source of infection of diseases caused by the larval stages of these parasites [4,5]
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