Recent advances in the search for new drugs for treatment of toxoplasmosis
ABSTRACT Although the combination of pyrimethamine with a sulfonamide is still very effective for treatment of toxoplasmosis the use of these two drugs immunocompromised individuals, particularly AIDS patienst, often results in a remarkable incidence of adverse reactions. There is, therefore, an urgent need for alternative drugs and newer therapeutic regimens for treatment of human toxoplasmosis. In this review, the in vitro and in vivo activities of a number of new drugs and new therapeutic regimens that have shown promising results in vartious experimental models for toxoplasmosisared discussed.
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ABSTRACT: Toxoplasma gondii lacks the capacity to synthesize purines de novo, and adenosine kinase (AK)-mediated phosphorylation of salvaged adenosine provides the major route of purine acquisition by this parasite. T. gondii AK thus represents a promising target for rational design of antiparasitic compounds. In order to further our understanding of this therapeutically relevant enzyme, an AK cDNA from T. gondii was overexpressed in E. coli using the pBAce expression system, and the recombinant protein was purified to apparent homogeneity using conventional protein purification techniques. Kinetic analysis of TgAK revealed Km values of 1.9 microM for adenosine and 54.4 microM for ATP, with a k(cat) of 26.1 min(-1). Other naturally occurring purine nucleosides, nucleobases, and ribose did not significantly inhibit adenosine phosphorylation, but inhibition was observed using certain purine nucleoside analogs. Adenine arabinoside (AraA), 4-nitrobenzylthioinosine (NBMPR), and 7-deazaadenosine (tubercidin) were all shown to be substrates of T. gondii AK. Transgenic AK knock-out parasites were resistant to these compounds in cell culture assays, consistent with their proposed action as subversive substrates in vivo.Molecular and Biochemical Parasitology 10/1999; 103(1):15-23. · 2.73 Impact Factor
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ABSTRACT: Toxoplasma gondii ME49 is an obligatory intracellular apicomplexa parasite that causes toxoplasmosis in humans, domesticated and wild animals. Waterborne outbreaks of acute toxoplasmosis worldwide reinforce the transmission of Toxoplasma gondii ME49 to humans through contaminated water and may have a greater epidemiological impact than previously believed. In the quest for drug and vaccine target identification subtractive genomics involving subtraction between the host and pathogen genome has been implemented for enlisting essential pathogen specific proteins. Using this approach, our analysis on both human and Toxoplasma gondii ME49 reveals that out of 7987 protein coding sequences of the pathogen, 950 represent essential non human-homologous proteins. Subcellular localization prediction & comparative-biochemical pathway analysis of these essential proteins gives a list of apicoplast-associated proteins having unique pathogen-specific metabolic pathway. These apicoplast-associated enzymes involved in fatty acid biosynthesis pathway of Toxoplasma gondii ME49, may be used as potential drug targets, as the pathway is vital for the protozoan's survival. Structure prediction of drug target proteins was done using fold based recognition method. Screening of the functional inhibitors against these novel targets may result in discovery of novel therapeutic compounds that can be effective against Toxoplasma gondii ME49. ABBREVIATIONS: DEG - Database of Essential Gene, KEGG - Kyoto Encyclopaedia of Genes and Genomes, KAAS - KEGG Automated Annotation Server, PFP - Protein Function Prediction, COG - Cluster of Orthologous Genes.Bioinformation 01/2011; 7(8):379-83. · 0.50 Impact Factor
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ABSTRACT: To investigate the role that cytokines may have in the development of toxoplasmic encephalitis (TE), the levels of gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12 ]p40[), IL-10, IL-6, IL-4, and IL-2 in serum were examined in CBA/Ca mice infected with a type II strain (ME49 or FORT) of Toxoplasma gondii. These strains caused severe (ME49) or mild (FORT) TE in CBA/Ca mice. From weeks 1 to 8 of infection, the levels of IL-6, IL-10, IL-12, IFN-gamma, and TNF-alpha in serum were significantly higher in the ME49-infected mice than in the FORT-infected mice, suggesting a role for these cytokines in the severity of TE in CBA/Ca mice. Since the ME49 and FORT strains are of the same type, our results suggest a role for the parasite in the development of severe TE through the increased production of proinflammatory cytokines and indicate that not all type II strains cause TE.Infection and Immunity 08/2003; 71(7):4171-4. · 4.07 Impact Factor