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Toxoplasma gondii is an intracellular parasite which can normally be cleared without complications in adult humans. However it can cause serious issues in patients who are immunosuppressed, for example upon undergoing organ transplants or cancer chemotherapy or suffering from AIDS. If contracted during pregnancy, congenital toxoplasmosis can occur with serious consequences for the foetus. Toxoplasma gondii can highjack the host melvalonate pathway, used for isoprenoid synthesis; this was one of the results of a recent study in Plos Pathogens from a research group in the University of Georgia in the USA. Fortunately the group also found that in mice, the parasite can be thwarted in this usurping of the host cell machinery by treatment with a combination of two drugs that already are known to be well-tolerated and safe in most people. The drugs used were the anti-cholesterol statin drug atorvastatin (Lipitor) and the osteoporosis bisphosphonate medication zoledronic acid (Zometa).

Isoprenoids are lipid compounds with essential roles in cell signalling, trafficking, energy metabolism, and protein translation. They are the targets of therapeutic agents in a range of diseases including cardiovascular disease, osteoporosis and bone metastases. Toxoplasma gondii has its own prokaryotic-type 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway for synthesis of isoprenoids such as isopentenyl diphosphate (IPP) and dimethyallyl diphosphate (DMAPP). The authors of the Plos Pathogens paper had previously shown that the key enzyme of downstream isoprenoid synthesis in T. gondii was an enzyme called farnesyl diphosphate synthase (TgFPPS), which is a dual purpose enzyme that can catalyse the condensation of IPP with three allylic substrates: DMAPP, geranyl diphosphate (GPP), and farnesyl disphosphate (FPP). However, in this study they found that when Toxoplasma gondii mutants null for this enzyme were used to infect mice they grew healthily and had an isoprenoid composition similar to their wild type counterparts. It was only when they were grown extracellularly that the effect of the mutation on growth phenotype became apparent, which suggested to the researchers that the parasite was using the host’s farnesyl diphosphate (FPP) and/or geranylgeranyl diphosphate (GGPP) in order to continue making isoprenoids and growing normally. This gave the researchers the idea of targeting both the host and parasite pathways with statin and bisphosphonate respectively, hence the use of Lipitor and Zometa. This combination of therapies resulted in cure of mice with lethal infection with the TgFPPs mutant. The authors suggest that this kind of double-hit strategy could have wider applicability in therapies directed against other parasites in the Apicomplexan family to which Toxoplasma gondii belongs. This includes the Plasmodium parasites which cause malaria and the Cryptosporidium parasites.

The theory needs to be researched further and subjected to rigorous testing in animals and humans before it could be adopted in human therapy for parasites, but if the results of this study are borne out it would be an attractive option as it involves already approved drugs known to be safe for humans. The signs are hopeful, for example early research suggests that combining atorvastatin with fosmidomycin, an antibiotic effective against malaria parasites, is more potent in combating malaria and may help lessen reduce drug resistance issues. The research continues.

Sources

LI, Z.-H., RAMAKRISHNAN, S., STRIEPEN, B. and MORENO, S.N.J., 2013. Toxoplasma gondii Relies on Both Host and Parasite Isoprenoids and Can Be Rendered Sensitive to Atorvastatin. PLoS Pathogens, 9 (10): e1003665 DOI: 10.1371/journal.ppat.1003665

LING, Y., LI, Z.-H., MIRANDA, K., OLDFIELD, E. and MORENO, S.N.J., 2007. The farnesyl-diphosphate/geranylgeranyl-diphosphatesynthase of Toxoplasma gondii is a bifunctional enzyme and a molecular target of bisphosphonates. J. Biol. Chem. 282, pp. 30804–30816.

University of Georgia. "Statin, osteoporosis drug combo may help treat parasitic infections." ScienceDaily, 17 Oct. 2013. [Accessed 19 Oct. 2013].