Novel N-Benzoyl-2-Hydroxybenzamide Disrupts Unique Parasite Secretory Pathway

• Published in: Antimicrobial Agents and Chemotherapy 2012-05, Vol.56 (5), p.2666-2682
• Main Authors: Fomovska, Alina, Huang, Qingqing, El Bissati, Kamal, Mui, Ernest J, Witola, William H, Cheng, Gang, Zhou, Ying, Sommerville, Caroline, Roberts, Craig W, 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, McLeod, Rima
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport; Adaptor Proteins, Vesicular Transport - antagonists & inhibitors; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; antagonists & inhibitors; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials; Antimalarials - chemical synthesis; Antimalarials - pharmacology; Antiprotozoal Agents; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - pharmacology; Benzamides; Benzamides - chemical synthesis; Benzamides - pharmacology; Biological and medical sciences; Cells, Cultured; chemical synthesis; clones; drug effects; drug resistance; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - parasitology; General aspects; genetics; granules; Humans; Infectious diseases; Inhibitory Concentration 50; Mechanisms of Action: Physiological Effects; Medical sciences; metabolism; Organelles; Organelles - drug effects; Organelles - genetics; Organelles - metabolism; parasites; Parasitic diseases; parasitology; pharmacology; Pharmacology. Drug treatments; physiology; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - genetics; Plasmodium falciparum - metabolism; Protein Transport; Protein Transport - drug effects; proteins; Protozoan Proteins; Protozoan Proteins - antagonists & inhibitors; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Quantitative Structure-Activity Relationship; Secretory Pathway; Secretory Pathway - drug effects; Secretory Pathway - physiology; Toxoplasma; Toxoplasma - drug effects; Toxoplasma - genetics; Toxoplasma - metabolism; Toxoplasma gondii; vacuoles
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.06450-11

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.