High-throughput screening of more than 30,000 compounds for anthelmintics against gastrointestinal nematode parasites.

Gastrointestinal nematodes (GINs) are amongst the most common parasites of humans, livestock, and companion animals. GIN parasites infect 1-2 billion people worldwide, significantly impacting hundreds of millions of children, pregnant women, and adult workers, thereby perpetuating poverty. Two benzimidazoles with suboptimal efficacy are currently used to treat GINs in humans as part of mass drug administrations, with many instances of lower-than-expected or poor efficacy and possible resistance. Thus, new anthelmintics are urgently needed. However, screening methods for new anthelmintics using human GINs typically have low throughput. Here, using our novel screening pipeline that starts with human hookworms, we screened 30,238 unique small molecules from a wide range of compound libraries, including ones with generic diversity, repurposed drugs, natural derivatives, known mechanisms of action, as well as multiple target-focused libraries (e.g., targeting kinases, GPCRs, and neuronal proteins). We identified 55 compounds with broad-spectrum activity against adult stages of two evolutionary divergent GINs, hookworms (