Function and relevance of the P-glycoproteins for anthelmintic resistance in Parascaris univalens

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Parasitic nematodes pose a considerable and widespread threat to human and animal health. Roundworms are a particularly pathogenic group of intestinal parasites that usually affect young animals. Horse foals and yearlings, for example, can become seriously or even fatally ill. The anthelmintics used to treat these parasites have lost much of their effectiveness over the past two to three decades. In the absence of new anthelmintic drugs or vaccines, anthelmintic resistance is increasingly threatening the health of the affected animal species and, in some cases, also of humans. In the foreground of the development of resistance are roundworms in animals and humans. The macrocyclic lactones (MLs) are the latest active substances used to combat horse worms, but they were already approved about 30 years ago. In particular, equine roundworms such as Parascaris univalens have now developed resistance to MLs worldwide. In order to counteract the further spread of resistant P. univalens populations in view of this situation, scientifically sound approaches, e.g. for the early detection of resistance but also for the reversion of resistance, are of crucial importance. To this end, we have been investigating drug efflux by transmembrane pumps called P-glycoproteins (Pgp). While in mammals there are usually only one or two Pgp genes, nematode genomes have many, P. univalens specifically ten, Pgps. Previous studies showed that Pgps are involved in the efflux of MLs in both parasitic and free-living nematodes (e.g. Caenorhabditis elegans). For P. univalens, we have described the sequences of all Pgp genes, collected first meaningful data on the transcription of the majority of these genes in different tissues, described putative gene polymorphisms for Pgp-11 associated with ML resistance, provided evidence for significant tissue-specific differences in Pgp-induced efflux of MLs, and described a new chemical lead structure as an inhibitor of nematode Pgps through targeted in vitro studies. In the continuation project applied for here, we intend to clarify the role of the most important Pgps in ML action and resistance with regard to the pharmacodynamics of different MLs and ML susceptibility in nematodes. In addition, it is our aim to show the expression of these Pgps in P. univalens at the cellular level in order to be able to compare the data collected in C. elegans on the function of the Pgps with their occurrence in the target organism. Furthermore, we want to use mass spectrometric analyses to show gradients of MLs between P. univalens tissues for the first time. The recent observations on a Pgp inhibitor lead structure will be the basis for characterisations of derivatised structures that specifically block nematodes but not host Pgps.