Transporter proteins of the malaria parasite are a core focus of our work. As well as being of fundamental importance to the biology of the parasite, these transporters are also important drug targets and mediators of resistance to existing antimalarials.
We have traditionally used a frog’s egg expression system to study transporter function, and have also recently introduced a more flexible and powerful yeast platform. As a first step, we are replicating our findings from other systems in yeast.
We have generated evidence that one transporter, PfATP6, is a target of artemisinins – the most widely used class of antimalarial drug. We are further characterising PfATP6 and the impact of naturally occurring genetic variants and mutations that may affect its function and sensitivity to artemisinins.
This work will help us to understand potential mechanisms of drug resistance and how they might be overcome, and may also suggest new ways in which PfATP6 could be targeted by drugs.
In addition, the parasite’s glucose transporter, PfHT, is a potentially important target for drug development. We have shown that the transporter can be specifically inhibited by glucose analogues, leading to death of parasites in culture and in a rodent model of malaria. We have been unable to knockout the PfHT gene, suggesting it essential for parasite survival – further validating PfHT as a drug target. We plan to use our resources to accelerate the search for PfHT inhibitors as potential drug leads.
Key publications
PfATP6
Eckstein-Ludwig U et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424(6951):957–61.
Uhlemann AC et al. A single amino acid residue can determine the sensitivity of SERCAs to artemisinins. Nat Struct Mol Biol. 2005;12(7):628–9.
Pulcini S et al. Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes. J Infect Dis. 2013;208(3):468–78.
PfHT
Joet T et al. Validation of the hexose transporter of Plasmodium falciparum as a novel drug target. Proc Natl Acad Sci USA. 2003;100(13):7476–9.
Slavic K et al. Use of a selective inhibitor to define the chemotherapeutic potential of the plasmodial hexose transporter in different stages of the parasite's life cycle. Antimicrob Agents Chemother. 2011;55(6):2824–30.
Slavic K et al. Life cycle studies of the hexose transporter of Plasmodium species and genetic validation of their essentiality. Mol Microbiol. 2010;75(6):1402–13.