Drug-Resistant Falciparum Malaria: Mechanisms, Consequences, and Challenges

Abstract

Malaria is the major parasitic disease in tropical developing countries, causing approximately 300 to 500 million febrile illnesses and at least 1.2 million deaths each year. Current antimalarial drugs and mosquito control programs constitute important measures against malaria, but these have limitations that must be met by research to develop new drugs, vaccines, and insecticides. The spread of drug-resistant malaria is a major obstacle for malaria control. Allelic replacement studies have demonstrated that chloroquine-sensitive parasites can be converted to the resistant phenotype using DNA transfection methods that introduce codons for these mutations into the expressed sequences of the wild-type pfcrt gene. Involvement of pfcrt as one of these genes is supported by studies showing that substitutions of Lys with Ile or Asn at amino acid position 76 of the transporter change parasite responses to both chloroquine and quinine. Quantitative trait loci (QTL) analysis of a genetic cross between P. falciparum clones has distinguished the additive effects of multiple genes in quinine response, including pfcrt, pfmdr1, and a third gene that is predicted to encode a sodium-hydrogen exchanger. Pyrimethamine and sulfadoxine are structurally similar to dihydrofolate and p-aminobenzoic acid (PABA), respectively, and act as competitive inhibitors of the dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) enzymes of P. falciparum.