The evolution of PfCRT from a carrier with a natural function to a drug transporting system in Plasmodium falciparum

• Applicant: Professor Dr. Michael Lanzer
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258470567

Drug resistance remains a pending problem in the control of malaria. Of particular concern is the reduced responsiveness of the human malaria parasite Plasmodium falciparum to quinolone antimalarial drugs. Quinoline derivatives have been used in malaria chemotherapy for more than a century. They are still indispensable, serving as partner drugs to artemisinin derivatives, which as artemisinin combination therapy comprise the current mainstay of malaria chemotherapy. A gene frequently contributing to response variations to quinolines, but also to a large number of structurally unrelated bioactive compounds, is pfcrt encoding a drug/metabolite carrier system. The objective of this project is i) to identify the natural substrate(s) of PfCRT; ii) to study how PfCRT has evolved from a metabolite carrier to a drug transporting system; iii) to develop tools to predict how PfCRT will mutate in the future when exposed to new drug challenges; and iv) to explore whether PfCRT can acquire a multi-drug resistance capability. The project brings together two groups with complementary expertise: a parasitology laboratory with a track record in drug resistance and an electrophysiology laboratory with a track record in the functional characterization of ion and metabolite transport systems. Both groups have successfully worked together. The project involves selection of PfCRT variants that confer response variations to diverse drugs in P. falciparum, the functional expression of PfCRT variants in Xenopus laevis oocytes, the investigation of the substrate specificity of PfCRT-mediated currents, the role of PfCRT in iron transport, transport studies using radioactive tracers, and live cell imaging. In depth knowledge about the structure and function of PfCRT will be crucial to efforts to maintain the clinical efficacy of quinoline antimalarial drugs and to develop effective strategies aimed at inhibiting the transport functions of PfCRT.

• DFG Programme: Research Grants
• International Connection: France
• Participating Person: Gabrielle Planelles, Ph.D.