Picture of person typing on laptop with programming code visible on the laptop screen

World class computing and information science research at Strathclyde...

The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by University of Strathclyde researchers, including by researchers from the Department of Computer & Information Sciences involved in mathematically structured programming, similarity and metric search, computer security, software systems, combinatronics and digital health.

The Department also includes the iSchool Research Group, which performs leading research into socio-technical phenomena and topics such as information retrieval and information seeking behaviour.

Explore

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

Fomovska, Alina and Huang, Qingqing and El Bissati, Kamal and Mui, Ernest J and Witola, William H and Cheng, Gang and Zhou, Ying and Sommerville, Caroline and Roberts, Craig W and Bettis, Sam 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 Pieroni, Marco and Stec, Jozef and Muench, Stephen P and Rice, David W and Kozikowski, Alan P and McLeod, Rima (2012) Novel N-Benzoyl-2-hydroxybenzamide disrupts unique parasite secretory pathway. Antimicrobial Agents and Chemotherapy.

Full text not available in this repository. Request a copy from the Strathclyde author

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.