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Parasitic nematodes infect billions of people and are mainly controlled by anthelmintic mass drug administration (MDA). While there are growing efforts to better understand mechanisms of anthelmintic resistance in human and animal populations, it is unclear how resistance mechanisms that alter susceptibility to one drug affect the interactions and efficacy of drugs used in combination. Mutations that alter drug permeability across primary nematode barriers have been identified as potential resistance mechanisms using the model nematode Caenorhabditis elegans. We leveraged high-throughput assays in this model system to measure altered anthelmintic susceptibility in response to genetic perturbations of potential cuticular, amphidial, and alimentary routes of drug entry. Mutations in genes associated with these tissue barriers differentially altered susceptibility to the major anthelmintic classes (macrocyclic lactones, benzimidazoles, and nicotinic acetylcholine receptor agonists) as measured by animal development. We investigated two-way anthelmintic interactions across C. elegans genetic backgrounds that confer resistance or hypersensitivity to one or more drugs. We observe that genetic perturbations that alter susceptibility to a single drug can shift the drug interaction landscape and lead to the appearance of novel synergistic and antagonistic interactions. This work establishes a framework for investigating combinatorial therapies in model nematodes that can potentially be translated to amenable parasite species. Author summary: Parasitic nematodes (roundworms) infect billions of people and animals worldwide and are mainly treated with a small number of anthelmintic drugs. The threat of drug resistance and the suboptimal nature of some single-drug treatments have prompted greater exploration of combinatorial drug regimens. However, we know very little about how these drugs may interact in exerting their anthelmintic effects or how these interactions are altered in the backdrop of resistance. We used the model nematode Caenorhabditis elegans to measure drug interactions across a panel of mutant strains that alter potential pathways of drug entry. Mutations in these pathways altered susceptibility to the major anthelmintic classes as measured by animal development. When drugs were administered in pairwise combinations, we observed that some mutations affecting single-drug susceptibility led to shifts in baseline drug antagonism and the appearance of drug synergies. This framework can potentially be translated to investigate drug interactions in amenable parasite species in the future. [ABSTRACT FROM AUTHOR]

Infection with Schistosoma parasitic flatworms ( Schistosoma haematobium, Schistosoma mansoni and Schistosoma japonicum ) causes the neglected tropical disease schistosomiasis. There is a need to identify new chemotherapies to treat these parasites, and G-protein coupled receptors (GPCRs) are a logical druggable targets to explore given they control key aspects of schistosome biology such as neuromuscular function and reproduction. Updated chromosome level genome assemblies for each of the three major species have recently been released. However, studies on these GPCRs require accurate, updated genome annotations. Here, we have re-annotated the GPCRs present in each of the three major schistosome species., (Copyright: © 2023 by the authors.)