title: Fosmidomycin uptake into Plasmodium and Babesia-infected erythrocytes is facilitated by parasite-induced new permeability pathways.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Parasitologie, Fachbereich Biologie, Philipps-Universität, Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Baumeister
authors.forename: Jochen
authors.initials: J
authors.lastname: Wiesner
authors.forename: Armin
authors.initials: A
authors.lastname: Reichenberg
authors.forename: Martin
authors.initials: M
authors.lastname: Hintz
authors.forename: Sven
authors.initials: S
authors.lastname: Bietz
authors.forename: Omar S
authors.initials: OS
authors.lastname: Harb
authors.forename: David S
authors.initials: DS
authors.lastname: Roos
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kordes
authors.forename: Johannes
authors.initials: J
authors.lastname: Friesen
authors.forename: Kai
authors.initials: K
authors.lastname: Matuschewski
authors.forename: Klaus
authors.initials: K
authors.lastname: Lingelbach
authors.forename: Hassan
authors.initials: H
authors.lastname: Jomaa
authors.forename: Frank
authors.initials: F
authors.lastname: Seeber
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism* / Q000494:pharmacology*; D001403:Babesia / Q000187:drug effects / Q000472:pathogenicity*; D015153:Blotting, Western; D002478:Cells, Cultured; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology*; D005455:Fluorescent Antibody Technique; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects / Q000472:pathogenicity*; D014122:Toxoplasma / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D000962:Antimalarials; D005578:Fosfomycin; C024640:fosmidomycin