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 Rice & 2 others Alan P Kozikowski, Rima McLeod

Research output: Contribution to journalArticle

22 Citations (Scopus)

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 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.
LanguageEnglish
JournalAntimicrobial Agents and Chemotherapy
DOIs
Publication statusPublished - 2012

Fingerprint

Secretory Pathway
Toxoplasma
Parasites
Vacuoles
Proteins
Chloroquine
Plasmodium falciparum
Clone Cells
Genome
2-hydroxybenzamide
Brain

Keywords

  • parasite secretory pathway
  • hydroxybenzamide

Cite this

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. / Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. In: Antimicrobial Agents and Chemotherapy. 2012.
@article{bd5b2117fc3b411c81d944e4514eb629,
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 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.",
keywords = "parasite secretory pathway , hydroxybenzamide",
author = "Alina Fomovska and Qingqing Huang and {El Bissati}, Kamal and Mui, {Ernest J} and Witola, {William H} and Gang Cheng and Ying Zhou and Caroline Sommerville and Roberts, {Craig W} and Sam Bettis and Prigge, {Sean T} and Afanador, {Gustavo A} and Hickman, {Mark R} and Lee, {Patty J} and Leed, {Susan E} and Auschwitz, {Jennifer M} and Marco Pieroni and Jozef Stec and Muench, {Stephen P} and Rice, {David W} and Kozikowski, {Alan P} and Rima McLeod",
year = "2012",
doi = "10.1128/AAC.06450-11",
language = "English",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",

}

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 2012, 'Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway' Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/AAC.06450-11

Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. / 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.

In: Antimicrobial Agents and Chemotherapy, 2012.

Research output: Contribution to journalArticle

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

Y1 - 2012

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 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.

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 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.

KW - parasite secretory pathway

KW - hydroxybenzamide

UR - http://www.scopus.com/inward/record.url?scp=84859805655&partnerID=8YFLogxK

U2 - 10.1128/AAC.06450-11

DO - 10.1128/AAC.06450-11

M3 - Article

JO - Antimicrobial Agents and Chemotherapy

T2 - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

ER -