Our project yielded important findings in anthelminthic drug discovery and development. First, we have conducted two Phase 2a dose selection trials with emodepside against Trichuris trichiura (trial 1) and hookworm (trial 2) in adults and a subsequent Phase 2b study to show whether emodepside is superior to albendazole against hookworm and T. trichiura. Our studies showed that emodepside demonstrated superiority, with an observed cure rate against hookworm at 96.6%, and was significantly higher compared with albendazole (cure rate 81.2%). The predicted cure rate against T. trichiura in the 5-mg emodepside group (85%) was higher than the predicted cure rate in the placebo group (10%). Second, we analyzed the microbiome from stool samples obtained of T. trichiura and hookworm-infected patients and found a gut microbiome mechanism responsible for treatment failures of the currently best available treatment, albendazole-ivermectin. We identified three bacterial enterotypes and show that pre-treatment enterotype is associated with efficacy of the combination treatment for both T. trichiura and hookworm infections. We found, that antibacterial activity of two anthelminthics, ivermectin and moxidectin is comparable to a selection of tested antibiotics, as observed by potency and dose dependence. Bacterial anthelminthic challenging in vitro resulted in decreased anthelminthic sensitivity. Further, adaptation to anthelminthics is associated with decreased antibiotic sensitivity towards three macrolides, a lincosamide, a fluoroquinolone, a tetracycline and two carbapenems. Third our work resulted in the discovery of a novel Trichuris species, Trichuris hominis. We provide genomic evidence that supports the establishment of drug resistance in humans. These findings challenge the current understanding of species within the Trichuris genus and have profound implications for both parasitology and public health. Overall, our work is of considerable public health relevance since it will ultimately result in better understanding of helminth infections and improved treatments for soil-transmitted helminthiasis. Fourth, we developed an electric-impedance based microwell-platform to automatically assess motility of hookworm third stage larvae. Electric- and light-based excitation was evaluated on the potential to repeatedly and accurately stimulate inactive larvae. Fluorescence light triggered an immediate stimulation of larvae, without negatively impacting their viability. While electric-based excitation was also capable of repeatedly stimulating larvae, it required a longer excitation period and voltages close to the platforms capacity. 10-15 larvae were adequate to produce sufficient signal and remain viable over a 72 hour analysis period, reducing larval consumption up to 60-fold compared to standard visual evaluation
