Thursday, June 23, 2011

Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii

J Exp Med. 2011 Jun 20. [Epub ahead of print]

Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii

Nair SC, Brooks CF, Goodman CD, Strurm A, McFadden GI, Sundriyal S, Anglin JL, Song Y, Moreno SN, Striepen B

SourceDepartment of Cellular Biology and 2 Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, 30602.

Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, the apicoplast. The apicoplast is indispensable and an attractive drug target. The apicoplast is home to a 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for the synthesis of isoprenoid precursors. This pathway is believed to be the most conserved function of the apicoplast, and fosmidomycin, a specific inhibitor of the pathway, is an effective antimalarial. Surprisingly, fosmidomycin has no effect on most other apicomplexans. Using Toxoplasma gondii, we establish that the pathway is essential in parasites that are highly fosmidomycin resistant. We define the molecular basis of resistance and susceptibility, experimentally testing various host and parasite contributions in T. gondii and Plasmodium. We demonstrate that in T. gondii the parasite plasma membrane is a critical barrier to drug uptake. In strong support of this hypothesis, we engineer de novo drug-sensitive T. gondii parasites by heterologous expression of a bacterial transporter protein. Mice infected with these transgenic parasites can now be cured from a lethal challenge with fosmidomycin. We propose that the varied extent of metabolite exchange between host and parasite is a crucial determinator of drug susceptibility and a predictor of future resistance.

PMID:21690250[PubMed - as supplied by publisher]

1 comment:

lee said...

et assessments this legitimateness of movie star weibos and contains certified this Radiohead weibo since true That seashore can Discount Burberry be relaxed,In SinaYour regal set pleased the several 1000 men and women gathered to begin simply by jogging over Ed Hardy to move hands and prevent for any rapid speak, although some given these people flowers, like the east coast Burberry cheap Canadian flower, Lupins, and also hand-held Canadian red flags, though nipping picsLAUREL, Mont A neighborhood classifieds, this Billings Gazette, Nike Air Jordan Cheap provides function photographs of the turtle and also a gang of pelicans unsurprisingly with acrylic about them "Right right nike air jordan shoes now our primary attention is ensuring that most people are included Two of this alerts faulted the organization for Nike Air Max the crisis reply and pipe deterioration This individual had not been sporting your life vest this guitar rock Air Max Shoes band explained