Anti-infectives targeting the isoprenoid pathway of Toxoplasma gondii

Isoprenoids are an extensive group of natural products with diverse structures consisting of various numbers of five carbon isopentenyl diphosphate (IPP) units.

We review here what is known about the isoprenoid pathway in T. gondii.

Recent primary literature is reviewed.

Genomic evidence points toward the presence of a 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway, similar to the one found in plants, which will produce isopentenyl diphosphate (IPP). The DOXP/MEP pathway has been validated as a target in the related Apicomplexan parasite Plasmodium. The DOXP/MEP pathway in Toxoplasma has not been characterized. Downstream in the pathway, the enzyme farnesyl diphosphate synthase (FPPS) has a central role in forming important intermediates since farnesyl diphosphate (FPP) is a precursor of critical molecules with fundamental biological function such as dolichols, heme a, cholesterol, farnesylated proteins and others. Strong evidence indicates that this enzyme is a valid target for drugs since bisphosphonates, which are specific FPPS inhibitors, inhibited parasite growth in vitro and in vivo. Our hypothesis is that the isoprenoid pathway constitutes a major novel target for the treatment of toxoplasmosis.