Distinct antischistosomal profiles of antimalarials and TRP agonists

Schistosomiasis control relies on praziquantel mass drug administration, but reports of field treatment failure and laboratory-selected resistance highlight the need for alternatives. Praziquantel activates a schistosome transient receptor potential (TRP) channel, TRPMPZQ. Alternative leads or chemotherapies include meclonazepam, which activates a distinct schistosome TRP channel, and the antimalarials artemether and mefloquine, whose flatworm targets are unknown. To compare molecular responses and assess cross-resistance, we conducted comparative RNA-seq and efficacy studies in infected mice. We profiled adult Schistosoma mansoni recovered 48 hours after artemether or mefloquine treatment and compared responses with existing datasets for TRP agonists praziquantel and meclonazepam. Transcriptional profiles clustered by drug class but showed largely distinct changes, with only 33 upregulated and 63 downregulated transcripts shared across treatments. Plexin domain-containing genes were strongly induced by both TRP agonists and, to a lesser extent, by antimalarials. Artemether downregulated gene families expressed in intestinal cells (saposins, cathepsins, and Bax inhibitor-like proteins), consistent with potential heme-dependent activity in the schistosome gut. Genes involved in glutamine metabolism, iron homeostasis and responses to oxidative damage were upregulated across multiple treatments. We evaluated all four treatments in mice infected with praziquantel-susceptible or resistant parasites. Praziquantel (200 mg/kg) reduced resistant male worm burdens by only 39.3%, versus 99.0% in susceptible parasites. Meclonazepam (83.0% versus 91.6% in susceptible parasites), mefloquine (99.1% versus 98.8%), and artemether (98.2% versus 99.4%) retained activity. The distinct transcriptional responses and retained activity against praziquantel-resistant parasites support further investigation of these compound classes as praziquantel alternatives or potential combination partners.