BSB PhD Exit Seminar: Amodiaquine resistance in the malaria parasite – revealing the How

Jamie Robertson, Lehane Group, BSB, RSB

The antimalarial drug amodiaquine has been around for nearly 60 years during which time it has been deployed as a monotherapy, then removed from recommendations due to toxicity fears, re-instated, and is now deployed in artemisinin-based combinations therapies to combat malaria. Incidences of malaria parasites developing resistance to amodiaquine have revealed associations with mutations in both the Plasmodium falciparum ‘chloroquine resistance transporter’ (PfCRT) and the ‘multidrug resistance protein 1’ (PfMDR1), though the mechanism of resistance has yet to be categorically shown and explained.

Utilising the Xenopus laevis oocyte expression system – an excellent way to functionally characterise proteins in the absence of confounding factors – I expressed clinically relevant mutant isoforms of both PfCRT and PfMDR1 and measured their amodiaquine transport properties. The data generated during my PhD candidature not only confirms and corroborates previous research into amodiaquine resistance in P. falciparum, but has also yielded novel insights into the role of PfCRT and PfMDR1 in the malaria parasite’s acquisition of amodiaquine resistance. While amodiaquine-resistant parasites harbour mutant isoforms of PfCRT and PfMDR1 the purpose of these mutations will be shown to cause the sequestration of amodiaquine in the parasite cytosol – away from amodiaquine’s site of action in the parasite’s digestive vacuole. My research also highlights important mutations in both PfCRT and PfMDR1; the prevalence of which should be monitored in malaria endemic regions. This will help inform the safest and most effective application of amodiaquine in future regimens.