TY - JOUR
T1 - Novel N-benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway
AU - Fomovska, Alina
AU - Huang, Qingqing
AU - El Bissati, Kamal
AU - Mui, Ernest J.
AU - Witola, William H.
AU - Cheng, Gang
AU - Zhou, Ying
AU - Sommerville, Caroline
AU - Roberts, Craig W.
AU - Bettis, Sam
AU - Prigge, Sean T.
AU - Afanador, Gustavo A.
AU - Hickman, Mark R.
AU - Lee, Patty J.
AU - Leed, Susan E.
AU - Auschwitz, Jennifer M.
AU - Pieroni, Marco
AU - Stec, Jozef
AU - Muench, Stephen P.
AU - Rice, David W.
AU - Kozikowski, Alan P.
AU - McLeod, Rima
PY - 2012/5
Y1 - 2012/5
N2 - 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 the low nanomolar range against T. gondii in vitro and in 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 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 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- resistant Plasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway of T. gondii, with the potential to be used as scaffolds in the search for improved compounds to treat the devastating diseases caused by apicomplexan parasites.
AB - 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 the low nanomolar range against T. gondii in vitro and in 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 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 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- resistant Plasmodium falciparum. Our studies reveal a novel class of compounds that disrupts a unique secretory pathway of T. gondii, with the potential to be used as scaffolds in the search for improved compounds to treat the devastating diseases caused by apicomplexan parasites.
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U2 - 10.1128/AAC.06450-11
DO - 10.1128/AAC.06450-11
M3 - Article
C2 - 22354304
AN - SCOPUS:84859805655
SN - 0066-4804
VL - 56
SP - 2666
EP - 2682
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 5
ER -