Plasmodium falciparum:Amplification and Overexpression ofpfmdr1Is Not Necessary for Increased Mefloquine Resistance

Lim, Amanda S.Y.; Galatis, Denise; Cowman, Alan F.

doi:10.1006/expr.1996.0077

Cited by 42 publications

(28 citation statements)

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“…One might be an interplay between mechanisms of mefloquine and chloroquine resistance as suggested by Lim and others. 18 In that study, selection for increased mefloquine resistance of P. falciparum FAC8 did not alter the copy number or the level of expression of pfmdr1. In addition, the level of chloroquine resistance of these selected parasites showed a small increase during selection.…”

Section: Discussionmentioning

confidence: 81%

Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand.

Chaiyaroj

Buranakiti²,

Angkasekwinai³

et al. 1999

Am J Trop Med Hyg

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Abstract. Resistance to quinoline-containing compound has been associated with the Plasmodium falciparum multidrug resistance 1 (pfmdr1) gene. We analyzed wild P. falciparum isolates with high levels of chloroquine and mefloquine resistance for their macrorestriction maps of chromosome 5 and sequence of pfmdr1. Two types of chromosome 5 amplification were found. Eleven of 62 resistant isolates displayed Bgl I fragments larger than 100 kb. Twenty-nine isolates possessed multiple copies of the fragments. We failed to detect any amplification of this region on chromosome 5 in 22 mefloquine-resistant isolates, suggesting that other mechanisms can mediate the mefloquine-resistant phenotype. There was no direct association between pfmdr1 mutations and chloroquine sensitivity. Resistant lines could have Asn-86 and Tyr-184 or Phe-184, the predicted sequence of those chloroquine-sensitive isolates. No mutation at Asn-1042 and Asp-1246 was detected among these chloroquine-resistant isolates. Therefore, a few base substitutions in the pfmdr1 gene may not be sufficient to account for all chloroquine-resistant phenotypes.In Thailand, malaria continues to be a major public health problem due to the emergence of multidrug-resistant organisms. Increasing levels and prevalence of Plasmodium falciparum resistance to choloroquine 1 and mefloquine 2-4 have been reported. This has made the treatment and prophylaxis of malaria increasingly complicated. Although new drugs and several drug combinations are being introduced, it is important to elucidate the molecular mechanism of aminoquinoline drug resistance to develop the appropriate strategies for malaria therapy.A P-glycoprotein homolog (Pgh 1) has been implicated in chloroquine-and mefloquine-resistant phenotypes of P. falciparum. [5][6][7][8] It is encoded by the P. falciparum multidrug resistance 1 (pfmdr1) gene and is localized on the membrane of the digestive vacuole of this parasite. 8,9 High levels of Pgh 1 expression have been shown in drug-resistant cell lines to confer a chloroquine-sensitive phenotype and in yeast to complement the ste 6 functions, 10 suggesting a role as a drug transporter. Controversy exists regarding the pfmdr 1 gene and chloroquine resistance from the work of Wellems and others 11 in that there is no linkage between pfmdr 1 and such resistance. In addition, in vitro selection of parasites for increased chloroquine resistance resulted in parasites with higher sensitivity to mefloquine. 12 Surprisingly, chromosome 5 of these parasite clones demonstrated deamplification and the expression of Pgh 1 was also decreased. 12 In subsequent drug selection studies, the higher levels of mefloquine resistance have been associated with amplification of pfmdr1. 8,13 Data from several field isolates with mefloquine resistance suggested that the amplification of pfmdr1 and an increase in mRNA expression is associated with natural resistance. Furthermore, cross-resistance to other related drugs such as halofantrine and quinine was also observed. [13][14][15] In this s...

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Section: Discussionmentioning

confidence: 81%

Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand.

Chaiyaroj

Buranakiti²,

Angkasekwinai³

et al. 1999

Am J Trop Med Hyg

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“…Attempts to answer the question related to pfmdr1 gene amplification also have a history of conflicting results. Some studies have reported increased copy numbers with selection for mefloquine resistance (5,12), while others have not (9,10).…”

Section: Discussionmentioning

confidence: 99%

Resistance to Antimalarials in Southeast Asia and Genetic Polymorphisms in pfmdr1

Pickard

Wongsrichanalai

Purfield

et al. 2003

Antimicrob Agents Chemother

256

231

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Resistance to antimalarial drugs is a public health problem worldwide. Molecular markers for drugresistant malaria, such as pfcrt and pfmdr1 polymorphisms, could serve as useful surveillance tools. To evaluate this possibility, sequence polymorphisms in pfcrt (position 76) and pfmdr1 (positions 86, 184, 1034, 1042, and 1246) and in vitro drug sensitivities were measured for 65 Plasmodium falciparum isolates from Thailand, Myanmar, Vietnam, and Bangladesh. The pfcrt Thr76 polymorphism was present in 97% of samples, consistent with observations that chloroquine resistance is well established in this region. Polymorphisms in pfmdr1 clustered into four specific patterns: the wild type (category I), a Tyr86 polymorphism only (category II), a Phe184 polymorphism only (category III), and Phe184 in combination with Cys1034 and/or Asp1042 (category IV). Isolates in categories I and III were more sensitive to chloroquine and more resistant to mefloquine, artesunate, and artemisinin than isolates in categories II and IV (P < 0.01). Mefloquine resistance was significantly more common in category I and III isolates than in category II and IV isolates, with a prevalence ratio of 14.95 (95% confidence interval, 3.88 to 57.56). These categories identified mefloquine resistance with a sensitivity and a specificity of 94 and 91%, respectively. The pfmdr1 gene copy number was measured by real-time PCR as a ratio of the amount of pfmdr1 DNA to the amount of lactate dehydrogenase (ldh) DNA. Eight samples had pfmdr1 DNA/ldh DNA ratios >3. The isolates in all 8 samples fell into categories I and III and were significantly more resistant to mefloquine, quinine, artemisinin, and artesunate and more sensitive to chloroquine than the isolates in the 57 samples with <3 copies of the gene (P < 0.001). Thus, measurement of pfmdr1 mutations and gene copy number may be useful for surveillance of mefloquine-resistant malaria in Southeast Asia.

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“…Clones of P. falciparum selected in vitro for high mefloquine resistance showed evidence of amplification and overexpression of pfmdr1 (14,31), whereas a decrease in resistance was associated with deamplification of the gene (2). However, in other studies no amplification was found in parasites selected for increased resistance (27,40,42). An association between amplification of pfmdr1 and mefloquine resistance has been claimed in some field investigations (34,35,51) but not in others (3,9).…”

mentioning

confidence: 87%

Genetics of Mefloquine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

Cravo

Carlton²,

Hunt

et al. 2003

Antimicrob Agents Chemother

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The genetic determinants of resistance to mefloquine in malaria parasites are unclear. Some studies have implied that amplification of, or mutations in, the multidrug resistance gene pfmdr1 in Plasmodium falciparum may be involved. Using the rodent malaria model Plasmodium chabaudi, we investigated the role of the orthologue of this gene, pcmdr1, in a stable mefloquine-resistant mutant, AS(15MF/3), selected from a sensitive clone. pcmdr1 exists as a single copy gene on chromosome 12 of the sensitive clone. In AS(15MF/3), the gene was found to have undergone duplication, with one copy translocating to chromosome 4. mRNA levels of pcmdr1 were higher in the mutant than in the parent sensitive clone. A partial genetic map of the translocation showed that other genes in addition to pcmdr1 had been cotranslocated. The sequences of both copies of pcmdr1 of AS(15MF/3) were identical to that of the parent sensitive clone. A cross was made between AS(15MF/3) and an unrelated mefloquine-sensitive clone, AJ. Phenotypic and molecular analysis of progeny clones showed that duplication and overexpression of the pcmdr1 gene was an important determinant of resistance. However, not all mefloquine-resistant progeny contained the duplicated gene, showing that at least one other gene was involved in resistance

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Plasmodium falciparum:Amplification and Overexpression ofpfmdr1Is Not Necessary for Increased Mefloquine Resistance

Cited by 42 publications

References 0 publications

Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand.

Analysis of mefloquine resistance and amplification of pfmdr1 in multidrug-resistant Plasmodium falciparum isolates from Thailand.

Resistance to Antimalarials in Southeast Asia and Genetic Polymorphisms in pfmdr1

Genetics of Mefloquine Resistance in the Rodent Malaria Parasite Plasmodium chabaudi

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