In vitro in-depth characterization of emodepside in combination with key anthelmintic drugs on soil-transmitted helminths

Resumen

ABSTRACT Despite the enormous disease burden, treatments are limited for soil-transmitted helminthiasis. The handful of anthelmintic drugs suffer from variable and often insufficient efficacy against the pathogens. Resistance development, caused by high drug pressure, is an ongoing concern. New treatments are needed, and combination therapies may represent a promising therapeutic strategy. We explored emodepside as a partner in combination therapy and characterized drug-interaction effects with key anthelmintics in vitro against different soil-transmitted helminths (STHs). Drug-interaction studies were carried out in human recombinant cytochromes P450 assays. Combination studies revealed species-, stage-, and drug-dependent interaction profiles. For benzimidazole-emodepside combinations, potentiation was only observed against Ancylostoma ceylanicum larvae, while against adult stages, up to threefold potentiation or synergy (ΣFIC < 0.9) was observed for Heligmosomoides polygyrus and Trichuris muris , especially for albendazole and albendazole sulfoxide. Combinations of emodepside with macrocyclic lactones showed mostly strong synergy against H. polygyrus larvae (ΣFIC 0.06–2.52), while other species trended toward antagonism (ΣFIC >1.5). Against adult stages, potentiation or synergism was observed in H. polygyrus and T. muris , while against Strongyloides ratti , only the moxidectin-emodepside combination was synergistic (ΣFIC 0.69–0.99). For nAChR agonists, levamisole showed the strongest effect against Necator americanus larvae, while oxantel pamoate exhibited potentiation or synergistic effects across multiple species and life stages. CYP450 inhibition assays reveal no relevant drug-drug interactions. This study provides a thorough evaluation of emodepside as a combination partner against soil-transmitted helminths in vitro , paving the way for in vivo studies and ultimately a novel combination therapy with emodepside against STH infections.