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

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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. (https://doi.org/10.1128/AAC.06450-11)

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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.

ORCID iDs

Fomovska, Alina, Huang, Qingqing, El Bissati, Kamal, Mui, Ernest J, Witola, William H, Cheng, Gang, Zhou, Ying, Sommerville, Caroline, Roberts, Craig W ORCID logoORCID: https://orcid.org/0000-0002-0653-835X, Bettis, Sam, Prigge, Sean T, Afanador, Gustavo A, Hickman, Mark R, Lee, Patty J, Leed, Susan E, Auschwitz, Jennifer M, Pieroni, Marco, Stec, Jozef, Muench, Stephen P, Rice, David W, Kozikowski, Alan P and McLeod, Rima;
CORE (COnnecting REpositories)