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.

  • Source
    • "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"
    [Show abstract] [Hide abstract]
    ABSTRACT: Drugs represent the primary treatment available for human malaria, as caused by Plasmodium spp. Currently approved drugs and antimalarial drug leads generally work against parasite enzymes or activities within infected erythrocytes. To reach their specific targets, these chemicals must cross at least three membranes beginning with the host cell membrane. Uptake at each membrane may involve partitioning and diffusion through the lipid bilayer or facilitated transport through channels or carriers. Here, we review the features of available antimalarials and examine whether transporters may be required for their uptake. Our computational analysis suggests that most antimalarials have high intrinsic membrane permeability, obviating the need for uptake via transporters; a subset of compounds appear to require facilitated uptake. We also review parasite and host transporters that may contribute to drug uptake. Broad permeability channels at the erythrocyte and parasitophorous vacuolar membranes of infected cells relax permeability constraints on antimalarial drug design; however, this uptake mechanism is prone to acquired resistance as the parasite may alter channel activity to reduce drug uptake. A better understanding of how antimalarial drugs reach their intracellular targets is critical to prioritizing drug leads for antimalarial development and may reveal new targets for therapeutic intervention.
    Frontiers in Pharmacology 05/2015; 6. DOI:10.3389/fphar.2015.00091
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Malaria is caused by species in the apicomplexan genus Plasmodium, which infect hundreds of millions of people each year and kill close to one million. While malaria is the most notorious of the apicomplexan-caused diseases, other members of eukaryotic phylum Apicomplexa are responsible for additional, albeit less well-known, diseases in humans, economically important livestock, and a variety of other vertebrates. Diseases such as babesiosis (hemolytic anemia), theileriosis and East Coast Fever, cryptosporidiosis, and toxoplasmosis are caused by the apicomplexans Babesia, Theileria, Cryptosporidium and Toxoplasma, respectively. In addition to the loss of human life, these diseases are responsible for losses of billions of dollars annually. Hence, the research into new drug targets remains a high priority. Ribonucleotide reductase (RNR) is an essential enzyme found in all domains of life. It is the only means by which de novo synthesis of deoxyribonucleotides occurs, without which DNA replication and repair cannot proceed. RNR has long been the target of antiviral, antibacterial and anti-cancer therapeutics. Herein, we review the chemotherapeutic methods used to inhibit RNR, with particular emphasis on the role of RNR inhibition in Apicomplexa, and in light of the novel RNR R2_e2 subunit recently identified in apicomplexan parasites.
    Current issues in molecular biology 07/2011; 14(1):9-26. · 6.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The malaria parasite has a chloroplast, which is a holdover from its algal past. The authors discuss the fascinating biology of this organelle and its promise for treatment in light of a seminal new study.
    PLoS Biology 08/2011; 9(8):e1001137. DOI:10.1371/journal.pbio.1001137 · 11.77 Impact Factor
Show more