NovelN-Benzoyl-2-Hydroxybenzamide Disrupts Unique Parasite Secretory Pathway

Abstract

ABSTRACTToxoplasma gondiiis a protozoan parasite that can damage the human brain and eyes. There are no curative medicines. Herein, we describe our discovery ofN-benzoyl-2-hydroxybenzamides as a class of compounds effective in the low nanomolar range againstT. gondii in vitroandin vivo. Our lead compound, QQ-437, displays robust activity against the parasite and could be useful as a new scaffold for development of novel and improved inhibitors ofT. gondii. Our genome-wide investigations reveal a specific mechanism of resistance toN-benzoyl-2-hydroxybenzamides mediated by adaptin-3β, a large protein from the secretory protein complex.N-Benzoyl-2-hydroxybenzamide-resistant clones have alterations of their secretory pathway, which traffics proteins to micronemes, rhoptries, dense granules, and acidocalcisomes/plant-like vacuole (PLVs).N-Benzoyl-2-hydroxybenzamide treatment also alters micronemes, rhoptries, the contents of dense granules, and, most markedly, acidocalcisomes/PLVs. Furthermore, QQ-437 is active against chloroquine-resistantPlasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway ofT. gondii, with the potential to be used as scaffolds in the search for improved compounds to treat the devastating diseases caused by apicomplexan parasites.