Mitochondria-targeted agents disrupt bioenergetics in parasitic nematodes.

Filarial parasites such as Brugia malayi and Dirofilaria immitis cause serious diseases in humans and animals, yet effective treatments that kill adult worms are limited and often toxic. We tested a new strategy that targets parasite mitochondria-the cell's energy source-using modified versions of two existing drugs, atovaquone (ATO) and honokiol (HNK). By attaching a mitochondrial targeting group, we created Mito-ATO and Mito-HNK, which enter parasite mitochondria more efficiently. These compounds were 10-50 times more potent than the original drugs, strongly inhibiting parasite movement and survival at very low doses. Mechanistic studies showed that the drugs disrupt mitochondrial energy production, leading to parasite death. Blocking glycolysis-a backup energy pathway-further enhanced efficacy. Notably, Mito-HNK was effective against heartworm larvae, supporting its potential use alongside current treatments. Overall, mitochondrial targeting offers a promising therapy for treating filarial infections.