Author: Donna Huber

Silvia Moreno and her research team at the University of Georgia’s Center for Tropical & Emerging Global Diseases and Department of Cellular Biology provided evidence that it is possible to develop a drug combination that acts synergistically by inhibiting host and parasite enzymes in a recently published article in Antimicrobial Agents and Chemotherapy.

What is toxoplasmosis?

Toxoplasmosis is caused by the pervasive intracellular Apicomplexan parasite Toxoplasma gondii. The parasite is found throughout the world and can infect humans and a number of animal species. In the U.S., people may contract it by consuming undercooked meats, especially pork, lamb, venison, or through contact with contaminated cat feces.

Human infections are usually asymptomatic but the parasite can persist in the form of tissue cysts. It has been estimated that 30–50% of the global population may be chronically infected with Toxoplasma. The immune system of a healthy individual can control the infection, but it can reactivate when there is immunosuppression due to organ transplant, cancer chemotherapy, or in people infected with HIV.

Toxoplasmosis is especially dangerous to the unborn fetus when the mother becomes infected during pregnancy as it can result in miscarriage or stillbirth. Surviving infants can suffer from visual, hearing, motor, cognitive, and other problems.

Some strains of T. gondii can cause severe ocular disease in people with a healthy immune system. Current drug therapies do not prevent disease progression that leads to blindness in ocular toxoplasmosis patients.

Toxoplasmosis represents a serious public health problem and no preventative or therapeutic vaccine is available for humans.

 

Need for better drug treatments for toxoplasmosis

Drugs presently used against toxoplasmosis do not eradicate chronic infection and as many as half of treated patients do not respond to the therapy. Additionally, a large number of people have an allergic reaction to the current treatment option. Furthermore, some the current drugs have recently become very expensive.

There is a need for safe and effective treatment.

Moreno and her team study the isoprenoid pathway to identify new drug targets. Isoprenoids are lipid compounds with many important functions. One particular step in this pathway has been identified as essential in T. gondii. A drug targeting this pathway could kill the parasite.

Drug combination may provide more effective and less expensive treatment

Moreno’s group proposes a double hit strategy of combining inhibitors of host and parasite pathways as a novel approach against toxoplasmosis. They have found a synergistic effect by combining new and potent sulfur-containing bisphosphonates, as well as other commercially available bisphosphonates, with several statins against a lethal infection of T. gondii using a virulence mouse model.

Bisphosphonates are widely used for the treatment of bone disorders. Previous studies by Moreno and her colleagues have shown that bisphosphonates inhibit the growth of a variety of protozoan parasites like T. gondii. There are a number of commercially available bisphosphonate drugs.

Statins are a class of drugs typically prescribed to lower cholesterol. They work by blocking a particular enzyme known as 3-hydroxy-methylglutaryl-coenzyme A reductase. As with the bisphosphonates, there are already a number of commercially available statins.

Bisphosphonates alone have been very effective when treating a lethal infection of T. gondii in mice. However, Moreno’s team found that combining bisphosphonates with the statin atorvastatin (Lipitor) was almost 3 times more effective under similar conditions of infection and treatment. Additionally, they found very low doses of both drugs could be used for treatment, which would significantly decrease the potential for adverse side effects.

This double hit strategy may be the key to effective treatment because the parasite not only makes its own isoprenoids, but it can also import them from the host. The ability to manipulate the host cell for its own benefit poses a challenge for drug development against toxoplasmosis. Therefore, inhibiting the host from producing this material along with inhibiting the parasite’s ability to create isoprenoids is an interesting and novel strategy for drug development.

Further studies for this novel therapeutic approach needed

This study demonstrates that early treatment is key to the cure of infection with a particular strain of T. gondii for acute infection. Since current treatments often fail to cure chronic infection Moreno and her group will next test this combination strategy in an established chronic infection mouse model.

Furthermore, Moreno predicts that this double-hit strategy of inhibiting both host and parasite pathways will work for other intracellular Apicomplexan parasites, such as the malaria-causing Plasmodium parasite. Additional studies will be needed to test this hypothesis.

An online version of this study is available: Li Z-H, Li C, Szajnman SH, Rodriguez JB, Moreno SNJ. 2017. Synergistic activity between statins and bisphosphonates against acute experimental toxoplasmosis. Antimicrob Agents Chemother 61:e02628-16. https://doi.org/10.1128/AAC.02628-16