Molecular epidemiology of malaria in Cameroon. X. Evaluation of PFMDR1 mutations as genetic markers for resistance to amino alcohols and artemisinin derivatives.

Abstract

Abstract. Mutations at five positions in the Plasmodium falciparum multidrug-resistance gene 1 (pfmdr1), initially thought to confer resistance to chloroquine, have been associated with in vitro resistance to amino alcohols and artemisinin derivatives in more recent studies. To assess the possible association between drug resistance phenotype and pfmdr1 polymorphisms and establish the baseline pfmdr1 sequence data in Yaoundé, Cameroon, the in vitro drug sensitivity pattern was determined for 64 clinical isolates by isotopic microtest. The pfmdr1 alleles were determined by a polymerase chain reaction and automatic sequencing. A large majority of isolates carried Tyr-86 (88%) and Phe-184 (91%) alleles. With the exception of one isolate with mixed codon 1246, all isolates had wild-type alleles Ser-1034, Asn-1042, and Asp-1246. There was no statistical association between codons 86 and 184 and in vitro response to chloroquine, amino alcohols, and artemisinin derivatives (P > 0.05). Our data do not seem to support the hypothesis that mutations in codons 86 and 184 influence the in vitro response to these drugs. Further monitoring of both in vitro response and pfmdr1 polymorphisms is required to evaluate the potential role played by other pfmdr1 alleles in the determination of drug resistance in Africa.

Antimalarial drugs: recent advances in molecular determinants of resistance and their clinical significance

“…1), as well as reduced lumefantrine IC 50 [38], a finding replicated in a separate study [39]. The lack of association between 3′ mutations and mefloquine IC 50 observed in other studies in SE Asia probably reflects reduced statistical power to detect effects when these SNPs are at low prevalence [40,41]. In South American parasites shown to have CDY alleles at the 3′ end, mefloquine IC 50 s are indeed low [42] and mefloquine remains predictably efficacious in such areas [43].…”

Limited Ability of Plasmodium falciparum pfcrt , pfmdr1 , and pfnhe1 Polymorphisms To Predict Quinine In Vitro Sensitivity or Clinical Effectiveness in Uganda

“…The single nucleotide polymorphisms in pfmdr1 that are common in Africa, N86Y, Y184F, and D1246Y, have had less marked impacts on quinine sensitivity in laboratory studies (44,48). In evaluations of clinical isolates, associations between pfmdr1 polymorphisms and in vitro quinine sensitivity have been uncertain, but evaluations considering the common polymorphisms seen in Africa have been limited (6). We recently evaluated pfmdr1 polymorphisms in the most and least sensitive of 196 isolates for which quinine sensitivity was measured in Uganda.…”

Role of Pfmdr1 in In Vitro Plasmodium falciparum Susceptibility to Chloroquine, Quinine, Monodesethylamodiaquine, Mefloquine, Lumefantrine, and Dihydroartemisinin

“…Two primer pairs were used to amplify Pfmdr1 fragments carrying the five key codons (31). A 590-bp fragment was amplified with a primer pair (sense, 5=-AGA GAA AAA AGA TGG TAA CCT CAG-3=; antisense, 5=-ACC ACA AAC ATA AAT TAA CGG-3=) to determine the sequences of codons 86 and 184 (MDR1-1), and a second fragment (968 bp) was amplified with a primer pair (sense, 5=-CAG GAA GCA TTTTAT AAT ATG CAT-3=; antisense, 5=-CGT TTAACA TCT TCC AAT GTT GCA-3=) to determine the sequences of codons 1034, 1042, and 1246 (MDR1-2) (31).…”