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Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

Parasitologie, Fachbereich Biologie, Philipps-Universität, Marburg, Germany.
PLoS ONE (Impact Factor: 3.53). 05/2011; 6(5):e19334. DOI: 10.1371/journal.pone.0019334
Source: PubMed

ABSTRACT Highly charged compounds typically suffer from low membrane permeability and thus are generally regarded as sub-optimal drug candidates. Nonetheless, the highly charged drug fosmidomycin and its more active methyl-derivative FR900098 have proven parasiticidal activity against erythrocytic stages of the malaria parasite Plasmodium falciparum. Both compounds target the isoprenoid biosynthesis pathway present in bacteria and plastid-bearing organisms, like apicomplexan parasites. Surprisingly, the compounds are inactive against a range of apicomplexans replicating in nucleated cells, including Toxoplasma gondii.
Since non-infected erythrocytes are impermeable for FR90098, we hypothesized that these drugs are taken up only by erythrocytes infected with Plasmodium. We provide evidence that radiolabeled FR900098 accumulates in theses cells as a consequence of parasite-induced new properties of the host cell, which coincide with an increased permeability of the erythrocyte membrane. Babesia divergens, a related parasite that also infects human erythrocytes and is also known to induce an increase in membrane permeability, displays a similar susceptibility and uptake behavior with regard to the drug. In contrast, Toxoplasma gondii-infected cells do apparently not take up the compounds, and the drugs are inactive against the liver stages of Plasmodium berghei, a mouse malaria parasite.
Our findings provide an explanation for the observed differences in activity of fosmidomycin and FR900098 against different Apicomplexa. These results have important implications for future screens aimed at finding new and safe molecular entities active against P. falciparum and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery.

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    • "ls outside of the inner ellipse ) . How do these compounds reach their intracellular targets to produce parasite killing ? As discussed below , three of these compounds , blasticidin S , leu - peptin , and fosmidomycin , cross the host erythrocyte mem - brane through a parasite - induced channel ( Hill et al . , 2007 ; Lisk et al . , 2008 , 2010 ; Baumeister et al . , 2011 ; Nair et al . , 2011 ) . Three approved antimalarial drugs , doxycycline , azithromycin , and lumefantrine , are predicted to be poorly absorbed ( filled circles outside outer ellipse , Figure 1A ) , but their uptake by infected cells has not been directly studied ; each has known problems with oral absorption , with facilitated or act"
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