Assessment of the association between three pfmdr1 point mutations and chloroquine resistance in vitro of Malaysian Plasmodium falciparum isolates

Cox-Singh, Janet; Singh, Balbir; Alias, A.; Abdullah, Mohammad Shukri

doi:10.1016/0035-9203(95)90045-4

Cited by 49 publications

(39 citation statements)

References 7 publications

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“…Our results are consistent with other studies of Pfmdr1 mutations among P. falciparum CQ-resistant strains conducted in Malaysia, 18 Guinea-Bissau, 19 Nigeria, 20 and subSaharan Africa. 21 These data, however, are in conflict with reports of lack of association between Pfmdr1 mutations and CQ resistance in P. falciparum using field isolates from Sudan, 22 Thailand, 23 and several laboratory strains.…”

Section: Malaria Casessupporting

confidence: 93%

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Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

Gómez-Saladín

Fryauff²,

Taylor³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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Abstract. Mutations in the Pfmdr1 gene are reported to be associated with chloroquine resistance in some Plasmodium falciparum isolates. A polymerase chain reaction/restriction fragment length polymorphism method was used for the detection of Pfmdr1 mutations in chloroquine-resistant field isolates of P. falciparum collected in Irian Jaya. The frequency of Pfmdr1 mutations was significantly higher in chloroquine-resistant P. falciparum parasites than background frequencies observed in the same location. The 7G8 mutation was identified in some parasites although always in a mixed genotype status. Chloroquine-resistant P. falciparum specimens were characterized using the World Health Organization 28-day criteria, supplemented by demonstrating adequate chloroquine absorption and genetic analysis.Resistance of Plasmodium falciparum to chloroquine (CQ) and other antimalarial drugs is a widespread phenomenon that challenges current control efforts. Since early reports in the late 1950s, CQ resistance has been identified in most regions of the world where malaria is endemic. This problem has been investigated in several islands of the Indonesian archipelago such as Lombok, 1 Java, 2 and Irian Jaya, [3][4][5] where the first Indonesian case of CQ-resistant P. falciparum was described. 6 To understand the mechanism of CQ resistance in malaria parasites, a search for the responsible gene(s) has been launched. In 1989 two P. falciparum genes homologous to the mammalian multiple drug resistance (MDR) gene were identified, mapped to chromosome V, 7 and named Pfmdr1 and Pfmdr2. 8 This discovery, coupled with the fact that the calcium channel blocker verapamil reverses CQ resistance, 9 gave support to the theory that a mechanism similar to multiple drug resistance in mammalian tumor cells, in which over expression and amplification of the MDR gene confers drug resistance to tumor cells via an efflux mechanism, operates in P. falciparum. The product of the Pfmdr1 gene, Pglycoprotein homolog 1 (Pgh1) has been localized to the membrane of the digestive vacuole of mature blood stage parasites. 10 This model predicted that the Pfmdr1 gene would be amplified and/or over expressed in CQ-resistant isolates but several studies obtained mixed results. [11][12][13][14][15] Considerable controversy has been generated by conflicting reports that tested a second model: that mutations in the Pfmdr1 gene confer CQ resistance. DNA sequencing of the Pfmdr1 gene from reference strains and field isolates has revealed several point mutations that correlated with CQ resistance. 16 These mutations were classed into two genotypes: the K1 genotype, resulting in an asparagine (Asn) to tyrosine (Tyr) change at position 86 and the 7G8 genotype, with four point mutations resulting in amino acid substitutions at positions 184, 1034, 1042, and 1246. Shortly after a rapid polymerase chain reaction (PCR) and restriction digest method for the detection of these two genotypes in field isolates was developed;17 field studies applied this technique and confirmed ...

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Section: Malaria Casessupporting

confidence: 93%

“…17 field studies applied this technique and confirmed the presence of these mutations in CQ-resistant isolates from Malaysia, 18 Guinea-Bissau, 19 Nigeria, 20 and subSaharan Africa. 21 No association, however, was found in isolates from Sudan, 22 Thailand, 23 Cambodia, 24 or 17 cultured strains.…”

mentioning

confidence: 91%

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

Gómez-Saladín

Fryauff²,

Taylor³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

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“…The discordance between the prediction based on the allelic form of pfmdr1 and chloroquine resistance has been shown elsewhere. [19][20][21][22][23][24][25] No mutation at Asn-1042 and Asp-1246 was detected among the Thai chloroquine-resistant isolates of P. falciparum, although earlier studies have reported this. 6 Similarly, Cox-Singh and others found no mutations of this type in isolates from Malaysia.…”

Section: Discussionmentioning

confidence: 77%

“…6 Similarly, Cox-Singh and others found no mutations of this type in isolates from Malaysia. 21 Thus, there is no simple association between mutation at positions 1042 and 1246 and chloroquine resistance.…”

Section: Discussionmentioning

confidence: 99%

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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“…Esta última mutación también se describió en muestras resistentes a la cloroquina en Brasil (18), pero no se encontró en muestras resistentes a la cloroquina de Asia y África (16,19).…”

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Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia

et al. 2007

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Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia Paula Montoya, Alberto Tobón, Silvia Blair, Jaime Carmona, Amanda Maestre Grupo de Malaria, Sede de Investigación Universitaria, Universidad de Antioquia, Medellín, ColombiaIntroducción. El gen pfmdr1 de Plasmodium falciparum se describió como un gen de resistencia a diversos antipalúdicos. Sin embargo, no se han estudiado el papel de su polimorfismo en la respuesta terapéutica al tratamiento con antipalúdicos en Colombia, ni su relación con paludismo grave. Objetivos. Este trabajo determinó la asociación entre los polimorfismos Asn 86 Tir y Asp 1246 Tir del gen pfmdr1 con la respuesta terapéutica a cloroquina, amodiaquina y mefloquina, en tres municipios antioqueños, y la asociación de estos polimorfismos con paludismo grave en muestras de pacientes del municipio de Tumaco. Materiales y métodos. Los polimorfismos del gen pfmdr1 se determinaron mediante amplificación de ácidos nucleicos y análisis con enzimas de restricción. Resultados. El alelo silvestre Asn 86 se encontró en 97% (137/141) de las muestras en el estudio de respuesta terapéutica a cloroquina, amodiaquina y mefloquina; no se observó ninguna asociación entre su presencia y la falla terapéutica como sí lo reportan otros autores. El alelo 1246 Tir se encontró en una alta proporción en el estudio de respuesta terapéutica, tanto en las muestras del día cero como en los del día de la falla después del tratamiento con los antipalúdicos. Conclusiones. Los polimorfismos 86 Tir y 1246 Tir en el gen pfmdr1 no son útiles como factores de predicción de falla terapéutica o paludismo grave en los municipios estudiados. Este estudio describe por primera vez la presencia del alelo 86 Tir en cuatro muestras clínicas de Suramérica.Palabras clave: Plasmodium falciparum/efectos de drogas, antipalúdicos/uso terapéutico, malaria, cloroquina, amodiaquina, mefloquina. Polymorphisms of the pfmdr1 gene in field samples of Plasmodium falciparum and their association with therapeutic response to antimalarial drugs and severe malaria in ColombiaIntroduction. The pfmdr1 gene of Plasmodium falciparum has been described as a gene conferring resistance to several antimalarial drugs. In particular, polymorphisms on specific codons have been associated with resistance and treatment failure with cloroquine, amodiaquine and mefloquine. However, the role of these polymorphisms in treatment response to antimalarials remains unexplored in Colombia. Furthermore, the relationship of these polymorphisms to severe malaria is unknown. Objective. This work studied the association of the Asn 86 Tyr and Asp 1246 Tyr pfmdr1 polymorphisms with response to cloroquine, amodiaquine and mefloquine treatment in three municipalities of Antioquia, and severe malaria cases from the municipality Tumaco. Materials and methods.The polymorphisms were assessed by nucleic acid amplification followed by restriction length polymorphism analysis. Result...

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Assessment of the association between three pfmdr1 point mutations and chloroquine resistance in vitro of Malaysian Plasmodium falciparum isolates

Cited by 49 publications

References 7 publications

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

Plasmodium falciparum mdr1 mutations and in vivo chloroquine resistance in Indonesia.

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

Polimorfismos del gen pfmdr1 en muestras clínicas de Plasmodium falciparum y su relación con la respuesta terapéutica a antipalúdicos y paludismo grave en Colombia

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