Poster Sessions

MB -7

Juliana Sa

J. Sa, O. Twu, K. Hayton, J. Skinner, V. Gopalan, J. Barnett, T. Wellems

Determining the Genetic Basis of Amodiaquine Resistance using its Active Metabolite

Amodiaquine (AQ) is extensively used and currently recommended by the World Health Organization to treat chloroquine (CQ) resistant malaria caused by the parasite Plasmodium falciparum. Treatment failures of AQ against CQ resistant (CQR) parasites suggest cross-resistance between these two drugs. We employed quantitative trait loci analysis of two P. falciparum genetic crosses to identify the genes underlying AQ resistance. QTL analysis revealed that pfcrt, the gene associated with CQ resistance, is responsible for cross-resistance between CQ and AQ. In addition, the multiple drug resistance gene pfmdr1 on chromosome 5 was found to play a role in modulating CQ and AQ responses in the cross between two CQR parasites. We also evaluated the effect of verapamil (VP), a chemo sensitizer known to reverse the CQR phenotype, in combination with each of the above drugs. VP chemosensitization was linked to a new locus on chromosome 7 containing a candidate gene encoding for a V-type ATPase. Results of this work establish for the first time a common genetic determinant for resistance to CQ and AQ. This has significant implications for malaria treatment recommendations as the continuous selection of CQ-resistant strains can lead to treatment failure and millions of deaths.