BSB PhD Exit Seminar: Structure-function studies of multidrug resistance transporters of the malaria parasite

Many genes that have been recently identified as determinants of drug resistance in the malaria parasite encode membrane transport proteins (also known as transporters).  Amongst these proteins are two key determinants of multidrug resistance – the ‘chloroquine resistance transporter’ (PfCRT) and the ‘multidrug resistance protein 1’ (PfMDR1).  Mutations in both transporters influence the parasite’s susceptibility to almost all currently deployed antimalarials. Moreover, mutations in both transporters are also associated with the development of collateral sensitivity in the malaria parasite – the phenomenon whereby the acquisition of resistance to one drug results in hypersensitivity to a second drug. However, elucidating the functions of these proteins, and ascertaining their contributions to drug action and drug resistance, can be very challenging due to the difficulties in achieving the expression and characterisation of transporters in heterologous systems.

The Xenopus laevis oocyte system offers many advantages for the functional characterisation of foreign transporters. Here, the factors involved in successfully expressing PfCRT and PfMDR1 in Xenopus laevis oocytes have been investigated, providing insights likely to be relevant to the expression of other malaria parasite transporters in this system. Characterisation of both PfCRT and PfMDR1 in Xenopus oocytes has elucidated insights into the molecular mechanisms by which the two proteins modulate the parasite’s susceptibility to several drugs, including chloroquine, quinine, lumefantrine, and amantadine. Exploiting these mechanisms of collateral drug sensitivity may assist with developing strategies that prevent or retard the spread of drug resistance.