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Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway

Fomovska, Alina and Huang, Qingqing and El Bissati, Kamal and Mui, Ernest J and Witola, William H and Cheng, Gang and Zhou, Ying and Sommerville, Caroline and Roberts, Craig W and Bettis, Sam and Prigge, Sean T and Afanador, Gustavo A and Hickman, Mark R and Lee, Patty J and Leed, Susan E and Auschwitz, Jennifer M and Pieroni, Marco and Stec, Jozef and Muench, Stephen P and Rice, David W and Kozikowski, Alan P and McLeod, Rima (2012) Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. Antimicrobial Agents and Chemotherapy.

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Abstract

Toxoplasma gondii is a protozoan parasite that can damage the human brain and eyes. There are no curative medicines. Herein, we describe our discovery of N-benzoyl-2-hydroxybenzamides as a class of compounds effective in low nanomolar range against T. gondii in vitro and in vivo. Our lead compound QQ-437 displays robust activity against the parasite, useful as a new scaffold for development of novel and improved inhibitors of T. gondii. Our genome-wide investigations reveal a specific mechanism of resistance to N-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 acidocalcisome/Plant-Like Vacuole (PLV). N-benzoyl-2-hydroxybenzamide treatment also alters micronemes, rhoptries, the contents of dense granules and most markedly acidocalcisomes/PLV. Furthermore, QQ-437 is active against chloroquine-resistant Plasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway of T. gondii, with potential to be used as scaffolds to discover improved compounds to treat the devastating diseases caused by apicomplexan parasites.