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

Alina Fomovska, Qingqing Huang, Kamal El Bissati, Ernest J. Mui, William H. Witola, Gang Cheng, Ying Zhou, Caroline Sommerville, Craig W. Roberts, Sam Bettis, Sean T. Prigge, Gustavo A. Afanador, Mark R. Hickman, Patty J. Lee, Susan E. Leed, Jennifer M. Auschwitz, Marco Pieroni, Jozef Stec, Stephen P. Muench, David W. RiceAlan P. Kozikowski, Rima McLeod

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)2666-2682
Number of pages17
JournalAntimicrobial agents and chemotherapy
Volume56
Issue number5
DOIs
StatePublished - May 1 2012

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Fomovska, A., Huang, Q., El Bissati, K., Mui, E. J., Witola, W. H., Cheng, G., Zhou, Y., Sommerville, C., Roberts, C. W., Bettis, S., Prigge, S. T., Afanador, G. A., Hickman, M. R., Lee, P. J., Leed, S. E., Auschwitz, J. M., Pieroni, M., Stec, J., Muench, S. P., ... McLeod, R. (2012). Novel N-benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. Antimicrobial agents and chemotherapy, 56(5), 2666-2682. https://doi.org/10.1128/AAC.06450-11