Drug uptake, sensitivity, interaction studies and resistance associated mutations in Plasmodium falciparum

QL Fivelman
Evidence is accumulating that polymorphisms in plmdr 1 and plcrt are involved in resistance to the quinoline based blood schizontocides and possibly artemisinin derivatives; and mutations in the cytochrome b gene (cytb) are strongly associated with resistance to atovaquone. With this in mind, we studied sensitivity, drug interactions and uptake in a range of Plasmodium lalciparum lines, including pfmdr 1 transfectants, plcrt mutated lines 106/1 and K76I, and an atovaquone-resistant isolate
more » ... istant isolate (NGATVOl) with a unique point mutation (tyr268asn). In vitro susceptibility studies and genetic characterisation supported the role of plmdr 1 and plert polymorphisms in the sensitivity of parasite lines to a range of structurally diverse antimalarials. Mutations in plcrt conferred chloroquine resistance modulated by changes in plmdr 1, while the wild-type genes were associated with reduced sensitivity to mefloquine, halofantrine, lumefantrine and dihydroartemisinin. Drug interaction studies in vitro using a modified isobologram method showed that dihydroartemisinin in combination with chloroquine, amodiaquine or the new bisquinoline piperaquine was antagonistic in all parasite lines examined. The response was synergistic when the drug was combined with mefloquine, halofantrine or lumefantrine against chloroquine-sensitive (wild-type plmdrl and plcrt), but additive against chloroquine-resistant parasite lines. However, in the 7G8-m
doi:10.17037/pubs.04646515 fatcat:gn7tjuydznewjippq5fh56c6se