title: Novel N-benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway.
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.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Institute of Genomics and Systems Biology, and The College, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Fomovska
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Huang
authors.forename: Kamal
authors.initials: K
authors.lastname: El Bissati
authors.forename: Ernest J
authors.initials: EJ
authors.lastname: Mui
authors.forename: William H
authors.initials: WH
authors.lastname: Witola
authors.forename: Gang
authors.initials: G
authors.lastname: Cheng
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Caroline
authors.initials: C
authors.lastname: Sommerville
authors.forename: Craig W
authors.initials: CW
authors.lastname: Roberts
authors.forename: Sam
authors.initials: S
authors.lastname: Bettis
authors.forename: Sean T
authors.initials: ST
authors.lastname: Prigge
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Afanador
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hickman
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
authors.forename: Susan E
authors.initials: SE
authors.lastname: Leed
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Auschwitz
authors.forename: Marco
authors.initials: M
authors.lastname: Pieroni
authors.forename: Jozef
authors.initials: J
authors.lastname: Stec
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Muench
authors.forename: David W
authors.initials: DW
authors.lastname: Rice
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Rima
authors.initials: R
authors.lastname: McLeod
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D020128:Inhibitory Concentration 50; D015388:Organelles / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology; D014122:Toxoplasma / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000962:Antimalarials; D000981:Antiprotozoal Agents; D001549:Benzamides; D015800:Protozoan Proteins