., a mouse malaria parasite. and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery

A Alkhalil

A Brown

A Gorenflot

A Zintl

AE Fouts

AM Dondorp

AM Gero

AMW Stead

AR Odom

Armin Reichenberg

AS Tarun

B Cooper

C Grauvogel

C Lambros

CJ Janse

D Giessmann

D Hill

David S. Roos

E Öhler

EF Pettersen

F Seeber

FJ Gamo

FJ Sangari

Frank Seeber

FW Muregi

G Lisk

G Pasvol

GA Biagini

Georges Snounou

H Ginsburg

H Jomaa

Hassan Jomaa

HM Staines

HP Kuemmerle

J Friesen

J Wiesner

Jochen Wiesner

Johannes Friesen

K Kirk

K Stelter

Kai Matuschewski

Klaus Lingelbach

L Deng

LM Henriksson

M Cassera

M Clastre

M Prudencio

MA Missinou

Martin Hintz

Maximilian Kordes

NV Dharia

O Bruna-Romero

O Silvie

Omar S. Harb

OS Harb

P Olliaro

PD Dobson

PD Karp

R Caspi

R Lizundia

R Moudy

RK Dhiman

S Baumeister

S Borrmann

SA Holstein

SA Ralph

Stefan Baumeister

Sven Bietz

T Kamiya

T Murakawa

T Sivakumar

T Tsuchiya

W Eisenreich

W Trager

W Wang

Y Ershov

Y Ling

Y Sakamoto

Y-H Woo

PLoS ONE

English

PubMed

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.  Methodology/Principal Findings: 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/Significance: 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

Baumeister, Stefan

Wiesner, Jochen

Reichenberg, Armin

Hintz, Martin

Bietz, Sven

Harb, Omar S.

Roos, David S.

Kordes, Maximilian

Friesen, Johannes

Matuschewski, Kai

Lingelbach, Klaus

Jomaa, Hassan

Seeber, Frank

Publication server of the Robert Koch Institute

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

Baumeister Stefan

Wiesner Jochen

Reichenberg Armin

Hintz Martin

Bietz Sven

Harb Omar S.

Roos David S.

Kordes Maximilian

Friesen Johannes

Matuschewski Kai

Lingelbach Klaus

Jomaa Hassan

Seeber Frank

Public Library of Science (PLOS)

Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

Baumeister, S.

Wiesner, J.

Reichenberg, A.

Hintz, M.

Bietz, S.

Harb, O.

Roos, D.

Kordes, M.

Friesen, J.

Matuschewski, K.

Lingelbach, K.

Jomaa, H.

Seeber, F.

MPG.PuRe

PLoS One

Publikationsserver des Robert Koch-Instituts

BackgroundHighly 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.Methodology/principal findingsSince 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/significanceOur 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

Omar S Harb

David S Roos

Directory of Open Access Journals

Fosmidomycin uptake into Plasmodium and Babesia-infected erythrocytes is facilitated by parasite-induced new permeability pathways.

Crossref

Max Planck Society eDoc Server

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

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Publikationsserver des Robert Koch-Instituts

Directory of Open Access Journals

Crossref

Public Library of Science (PLOS)

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