Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance.
Molecular determinants of antimalarial drug resistance are useful and informative tools that complement phenotypic assays for drug resistance. They also guide the design of strategies to circumvent such resistance once it has reached levels of clinical significance. Established resistance to arylaminoalcohols such as mefloquine and lumefantrine in SE Asia is mediated primarily by gene amplification of the P. falciparum drug transporter, pfmdr1. Single nucleotide polymorphisms in pfmdr1, whether assessed in field isolates or transfection experiments, are associated with changes in IC(50) values (to arylaminoalcohols and chloroquine), but not of such magnitude as to influence clinical treatment outcomes. Recently described emerging in vitro resistance to artemisinins in certain areas correlates with mutations in the SERCA-like sequence PfATP6 and supports PfATP6 as a key target for artemisinins.
Woodrow
C J
CJ
Department of Cellular and Molecular Medicine, Centre for Infection, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, UK.
Krishna
S
S
D000349:Africa / Q000453:epidemiology; D000605:Amino Alcohols / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D001210:Asia, Southeastern / Q000453:epidemiology; D001692:Biological Transport / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000502:physiology; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D018432:Drug Resistance, Multiple / Q000235:genetics / Q000502:physiology; D004359:Drug Therapy, Combination; D005784:Gene Amplification; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000453:epidemiology; D015767:Mefloquine / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D026901:Membrane Transport Proteins; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins; D011803:Quinine / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology
D000605:Amino Alcohols; D000962:Antimalarials; D037621:Artemisinins; D000252:Calcium-Transporting ATPases; D002738:Chloroquine; D015767:Mefloquine; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015800:Protozoan Proteins; D011803:Quinine; D012717:Sesquiterpenes; C513500:ATP6 protein, Plasmodium falciparum; C513498:Mdr1 protein, Plasmodium falciparum; C513499:Mdr2 protein, Plasmodium falciparum; C416369:PfCRT protein, Plasmodium falciparum; C031327:artemisinin