Genetic and Biochemical Aspects of Drug Resistance in Malaria Parasites

Abstract

Drug resistance is one of the major factors contributing to the resurgence of malaria, especially resistance to the most affordable drugs such as chloroquine and Fansidar, a combination drug of pyrimethamine and sulfadoxine. Understanding the mechanisms of such resistance and developing new treatments, including new drugs, are urgently needed. Great progress has been made recently in studying the mechanisms of drug action and drug resistance in malaria parasites, particularly in Plasmodium falciparum. These efforts are highlighted by the demonstration of mutations in the parasite dihydrofolate reductase and dihydropteroate synthase genes conferring resistance to pyrimethamine and sulfadoxine, respectively, and by the recent discovery of mutations in the gene coding for a putative transporter, PfCRT, conferring resistance to chloroquine. Mutations in a homologue of a human multiple-drug-resistant gene, pfmdr1, have also been shown to be associated with responses to multiple drugs. However, except in the case of resistance to antifolate drugs, the mechanisms of action and resistance to most drugs currently in use are essentially unknown or are being debated. Additionally, novel mechanisms of resistance exist in different malaria parasites, complicating the process of developing new drugs and treatment strategies. Here we summarise the progress made in drug resistance research in malaria parasites over the past 20 years, emphasising the most recent developments in the genetics of drug resistance.

Discordant Patterns of Genetic Variation at Two Chloroquine Resistance Loci in Worldwide Populations of the Malaria Parasite Plasmodium falciparum

“…CQR Pfcrt 76T and Pfmdr1 86Y alleles (28), suggesting a joint contribution of these two genes to the CQR phenotype, the results of other studies have suggested that additional parasite genes are likely to be involved (11,36).…”

Frequency Distribution of Antimalarial Drug Resistance Alleles among Plasmodium falciparum Isolates from Gezira State, Central Sudan, and Gedarif State, Eastern Sudan

“…[1][2][3] In addition, point mutations in P. falciparum multi-drug resistance gene 1 ( pfmdr1 ) (e.g., N86Y, Y183F, S1034C, N1042D, and D1246Y) have been shown to modulate CQ resistance 4 and possibly lumefantrine resistance. 5 Similarly, resistance of malaria parasites to antifolates is conferred by mutation in dihydrofolate reductase (DHFR) and dihydropteroate syntase (DHPS), two enzymes involved in the parasite's folate synthesis.…”

Different Patterns of pfcrt and pfmdr1 Polymorphisms in P. falciparum Isolates from Nigeria and Brazil: The Potential Role of Antimalarial Drug Selection Pressure

“…11 Two pfmdr1 mutant alleles/haplotypes occur in CQR strains from different geographic regions; 86Y-184Y-1034S-1042N-1246D predominant in Asia and Africa and 86N-184F-1034C-1042D-1246Y predominant in South America. 11,12 However, a number of field studies have observed a significant non-random association between the CQR pfcrtThr76 and pfmdr1Tyr86 alleles, 13,14 suggesting a joint contribution of these two genes to the CQR phenotype. In this study, we investigated the frequency of pfcrt haplotypes in two different regions of West Africa and South America where chloroquine (CQ) and amodiaquine (AQ), respectively, were widely used.…”