Antimicrob Agents Chemother. 2012 Feb 21. [Epub ahead of print]
Novel N-Benzoyl-2-hydroxybenzamide Disrupts Unique Parasite Secretory Pathway.
Fomovska A, Huang Q, El Bissati K, Mui EJ, Witola WH, Cheng G, Zhou Y, Sommerville C, Roberts CW, Bettis S, Prigge ST, Afanador GA, Hickman MR, Lee PJ, Leed SE, Auschwitz JM, Pieroni M, Stec J, Muench SP, Rice DW, Kozikowski AP, McLeod R.
Department of Ophthalmology and Visual Sciences, Pediatrics (Infectious Diseases), Committees on Genetics, Immunology, and Molecular Medicine, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, Illinois 60637, United States.
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.
PMID: 22354304 [PubMed - as supplied by publisher]