Repurposing drugs to fight deadly infections
By Bill Sullivan, PhD
New drugs are urgently needed to fight life-threatening infections caused by single-celled parasites like Plasmodium, which causes malaria, and Toxoplasma, which causes toxoplasmosis. Transmitted by mosquitoes, malaria kills up to a million people a year and the parasite is quickly developing resistance to antimalarial drugs. Transmitted by cats, toxoplasmosis can cause opportunistic disease in immunocompromised individuals, but can also be transmitted from mother to child during pregnancy, causing miscarriage or birth defects.
The Toxoplasma parasite permanently resides in over 30 percent of people around the world in the form of latent tissue cysts. People become infected by inhaling or accidentally ingesting parasite oocysts shed by infected cats; oocysts can also be picked up from contaminated vegetables or water. Tissue cysts present in other animals also can infect humans if meat products are not cooked sufficiently.
Healthy people tend not to show symptoms of infection, but unbeknownst to them, the parasites will form tissue cysts inside their brain cells, where they remain until the host’s dying day. Some researchers have linked this form of chronic toxoplasmosis to neurological issues, including predisposition to schizophrenia or rage disorder. The tissue cysts are also the source of reactivated infection in immune compromised patients. The drug Daraprim is used to put reactivated toxoplasmosis into remission, but it does not eradicate the tissue cysts.
No approved drug has been shown to get rid of the tissue cysts in the brain, and this stage of the infection has long been considered to be untreatable. Our laboratory studies the molecular mechanisms that the parasite uses to switch back and forth between replicating and latent stages, in hopes of finding new ways to eliminate the parasite from the body. In collaboration with Dr. Ronald Wek, our laboratory has shown that a key process in the development of these tissue cysts involves the regulation of protein synthesis. We demonstrated that an initiation factor called eIF2 becomes phosphorylated when the Toxoplasma parasites are induced to form tissue cysts2. The phosphorylation of eIF2 causes different proteins to be made by the parasite.
Recently, an old blood pressure medication called guanabenz was shown to interfere with the phosphorylation status of eIF2 in other species. Given the role of eIF2 phosphorylation in parasite latency, we tested if guanabenz might be useful against Toxoplasma infection using a mouse model3. After treating chronically infected mice with guanabenz for 20 days, we counted the number of parasite cysts in their brains. The results showed that there were significantly fewer cysts in the guanabenz-treated mice compared to mice that didn’t receive the drug. This represents the first evidence of an approved drug being capable of reducing Toxoplasma brain cysts and provides a ray of hope that the chronic stage of infection can be eliminated from the billions of people carrying it.
In addition to combating Toxoplasma, we also showed that guanabenz had potent activity against malaria parasites. Since guanabenz is already FDA-approved, it is hoped that this drug can be repurposed quickly as a novel treatment for these parasitic infections.
1. Lead image taken by Imaan Benmerzouga.
2. Translation regulation by eukaryotic initiation factor-2 kinases in the development of latent cysts in Toxoplasma gondii.
Narasimhan J, Joyce BR, Naguleswaran A, Smith AT, Livingston MR, Dixon SE, Coppens I, Wek RC, Sullivan WJ Jr.
J Biol Chem. 2008 Jun 13;283(24):16591-601.
3. Guanabenz repurposed as an antiparasitic with activity against acute and latent toxoplasmosis.
Benmerzouga I, Checkley LA, Ferdig MT, Arrizabalaga G, Wek RC, Sullivan WJ Jr.
Antimicrob Agents Chemother. 2015 Nov;59(11):6939-45.