Use of a Selective Inhibitor to Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite's Life Cycle

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2011 Mar 16

PMID 21402842

Citations 20

Authors

Ksenija Slavic

Michael J Delves

Miguel Prudencio

Arthur M Talman

Ursula Straschil

Elvira T Derbyshire

Zhengyao Xu

Robert E Sinden

Maria M Mota

Christophe Morin

Rita Tewari

Sanjeev Krishna

Henry M Staines

Affiliations

Soon will be listed here.

Abstract

During blood infection, malarial parasites use D-glucose as their main energy source. The Plasmodium falciparum hexose transporter (PfHT), which mediates the uptake of D-glucose into parasites, is essential for survival of asexual blood-stage parasites. Recently, genetic studies in the rodent malaria model, Plasmodium berghei, found that the orthologous hexose transporter (PbHT) is expressed throughout the parasite's development within the mosquito vector, in addition to being essential during intraerythrocytic development. Here, using a D-glucose-derived specific inhibitor of plasmodial hexose transporters, compound 3361, we have investigated the importance of D-glucose uptake during liver and transmission stages of P. berghei. Initially, we confirmed the expression of PbHT during liver stage development, using a green fluorescent protein (GFP) tagging strategy. Compound 3361 inhibited liver-stage parasite development, with a 50% inhibitory concentration (IC₅₀) of 11 μM. This process was insensitive to the external D-glucose concentration. In addition, compound 3361 inhibited ookinete development and microgametogenesis, with IC₅₀s in the region of 250 μM (the latter in a D-glucose-sensitive manner). Consistent with our findings for the effect of compound 3361 on vector parasite stages, 1 mM compound 3361 demonstrated transmission blocking activity. These data indicate that novel chemotherapeutic interventions that target PfHT may be active against liver and, to a lesser extent, transmission stages, in addition to blood stages.

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