Triazine Inhibits
            <i>Toxoplasma gondii</i>
            Tachyzoites In Vitro and In Vivo

Mui, Ernest; Jacobus, David P.; Milhous, Wilbur K.; Schiehser, Guy A.; Hsu, Honghue; Roberts, Craig W.; Kirisits, Michael J.; McLeod, Rima

doi:10.1128/aac.49.8.3463-3467.2005

Cited by 30 publications

(33 citation statements)

References 15 publications

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“…The RH strain of T. gondii was maintained by serial passage in human foreskin fibroblast (HFF) (15) that were grown to a confluent monolayer in glass Petri dishes (150 mm diameter). Cells were cultured in IMDM supplemented with 10% fetal calf serum (FCS) inactivated at 56°C for 1 hour, 1 IU of penicillin/ml, 100 μg/ml of streptomycin, 0.25 μg/ml of amphotericin B, and 10 mM L-glutamine at 37°C with 5% CO 2 .…”

Section: Toxoplasma Cell Pellet Preparationmentioning

confidence: 99%

Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

et al. 2007

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Analysis of the polar lipids of Toxoplasma gondii by electrospray ionization tandem mass spectrometry provides a detailed picture of the lipid molecular species of this parasitic protozoan. Most notably, T. gondii contains a relatively high level, estimated to about 2% of the total polar lipid, of ceramide phosphoethanolamine. The ceramide phosphoethanolamine has a fatty amide profile with only 16-and 18-carbon species. Compared with the host fibroblasts in which it was grown, T. gondii also has higher levels of phosphatidylcholine, but lower levels of sphingomyelin and phosphatidylserine. Analysis at the molecular species level indicated that T. gondii has greater amounts of shorter-chain fatty acid in its polar lipid molecular species than the host fibroblasts. Shorter-chain fatty acids with a combined total of 30 or fewer acyl carbons make up 21% of Toxoplasma's, but only 3% of the host's, diacyl phosphatidylcholine. Furthermore, diacyl phosphatidylcholine with two saturated acyl chains with 12, 14, or 16 carbons make up over 11% of parasite phosphatidylcholine, but less than 3% of the host phosphatidylcholine molecular species. The distinctive T. gondii tachyzoite lipid profile may be particularly suited to the function of parasitic membranes and the interaction of the parasite with the host cell and the host's immune system. Combined with T. gondii genomic data, these lipidomic data will assist in elucidation of metabolic pathways for lipid biosynthesis in this important human pathogen. † This work was supported by NIH NIAID R01s AI27530, AI43228, AI071319, the Research to Prevent Blindness Foundation, and gifts from the Kieweit, Blackmon, Brennan, Koshland, Langel, Morel, Rosenstein, Cussen, Kapnick, and Rooney-Alden families. Work and instrument acquisition at the Kansas Lipidomics Research Center Analytical Laboratory were supported by grants from NSF (MCB 0455318 and DBI 0521587) and NSF's EPSCoR program (EPS-0236913), with matching support from the State of Kansas through Kansas Technology Enterprise Corporation and Kansas State University, as well from NIH grant P20 RR016475 from the INBRE program of the National Center for Research Resources. This is contribution 07-308-J from the Kansas Agricultural Experiment Station.*To whom correspondence should be addressed: Rima McLeod, M.D., The University of Chicago, AMBH S206; 5841 S Maryland Avenue, Chicago, Illinois 60637, Email: rmcleod@midway.uchicago.edu. 1 Abbreviations: ceramide, Cer; ceramide phosphoethanolamine, PE-cer; dihexosylceramide, Dihex-cer; electrospray ionization, ESI; mass spectrometry, MS; phosphatidic acid, PA; phosphatidylcholine, PC; (alkyl or alkenyl)/acyl glycerophosphocholine, ePC; phosphatidylethanolamine, PE; (alkyl or alkenyl)/acyl glycerophosphoethanolamine, ePE; phosphatidylinositol, PI; (alkyl or alkenyl)/ acyl glycerophosphoserine, ePS; Hexosyl ceramide, Hex-cer; phosphatidylserine, PS; sphingomyelin, SM; tandem mass spectrometry, MS/MS. Toxoplasma gondii infects 2-3 billion people throughout the world and is known ...

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Section: Toxoplasma Cell Pellet Preparationmentioning

confidence: 99%

Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

et al. 2007

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“…This RH-ERP line was used to develop procedures for plaque formation on monolayers of host cells, providing a very useful in vitro assay that captures a combination of invasion, replication, egress, and spread. The ability of T. gondii to form such plaques has been used to generate temperature sensitive mutants (36), define the molecular basis of various chemically derived mutants (33)(34)(35), test drug sensitivity of parasite strains (29,30), develop genetic transformation (45), and to test the phenotype of gene knockouts (20).…”

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confidence: 99%

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

et al. 2009

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Toxoplasma gondii has an unusual population structure consisting of three clonal lineages that predominate in North America and Europe. This simple pattern has encouraged the use of only a few laboratory isolates that are representative of each lineage. Principle among these is the type I RH strain, originally isolated from a child with encephalitis some 70 years ago. Comparison of different passages of the RH strain that have been propagated differently over the intervening time period revealed that the commonly used clonal line called RH-ERP was not representative of natural isolates of the type I lineage. Notably, RH-ERP formed much larger plaques than other type 1 strains, including a separate, earlier derived isolate of the RH strain. The RH-ERP variant also showed enhanced extracellular survival, faster growth, and decreased differentiation compared to the prototype type I strain GT1. Comparison of gene expression differences in the RH-ERP line revealed that several ABC transporters were upregulated, which may provide a growth advantage in vitro. These findings illustrate that dramatic phenotypic changes can arise in laboratory strains, emphasizing the need for comparison with recent clinical isolates.

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“…JPC-2067-B (10) is more efficacious than pyrimethamine against T. gondii tachyzoites and is cidal in cell culture. All three T. gondii clonal types and isolates (RH, Me49 and VEG) have identical amino acid sequences for TgDHFRs, highlighting its conserved nature as a promising target for anti-Toxoplasma agents [66].…”

Section: Dhfr -Revival Of a Resistance-compromised Targetmentioning

confidence: 99%

“…WR99210 (9) and related triazine JPC-2067-B (10, Fig. 1) are have been investigated as highly effective inhibitiors of TgDHFR (IC50 <10 nM) and T. gondii in vitro and in vivo [65,66]. JPC-2067-B (10) is more efficacious than pyrimethamine against T. gondii tachyzoites and is cidal in cell culture.…”

Section: Dhfr -Revival Of a Resistance-compromised Targetmentioning

confidence: 99%

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

Gordon¹,

Fishwick²,

McPhillie

2016

CTMC

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Abstract:Since the recent renaissance of phenotypic screening in the field of protozoan drug discovery, is there still an opportunity for the structure-based design of new anti-protozoan agents? Target-based approaches should be used in parallel to phenotypic screening to strengthen the pipeline of anti-protozoan agents. We give an overview of the protozoan drug discovery landscape highlighting four protein targets of interest: cytochrome bc1, dihydroorotate dehydrogenase, dihydrofolate reductase and calcium-dependent protein kinase 1. We discuss recent structure-based design efforts to inhibit these targets, reviewing their crystal structures and their ability to accommodate potent and selective compounds. Finally, we discuss future opportunities to apply structure-based methods to promising molecular targets within protozoan parasites discovered using chemical genomics.

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Triazine Inhibits Toxoplasma gondii Tachyzoites In Vitro and In Vivo

Cited by 30 publications

References 15 publications

Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

Lipidomic Analysis of Toxoplasma gondii Reveals Unusual Polar Lipids

Phenotypic and Gene Expression Changes among Clonal Type I Strains of Toxoplasma gondii

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

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