Amplification of pfmdr1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand

Wilson, Craig M.; Volkman, Sarah K.; Thaithong, Sodsri; Martin, R. K.; Kyle, Dennis E.; Milhous, Wilbur K.; Wirth, Dyann F.

doi:10.1016/0166-6851(93)90252-s

Cited by 255 publications

(173 citation statements)

References 23 publications

Supporting

Mentioning

159

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, cross-resistance to other related drugs such as halofantrine and quinine was also observed. [13][14][15] In this study, we demonstrated that there was no absolute correlation of amplification of the region of the genome surrounding pfmdr1 in P. falciparum isolates with mefloquine resistance from Thailand. Macrorestriction maps showed that there were 2 patterns of amplification.…”

mentioning

confidence: 61%

“…Thus, no inverse relationship involving pfmdr1 between mefloquine and chloroquine was shown in mefloquine-selected FAC8 lines as previously reported. [12][13][14] Several investigators have also suggested that resistance to mefloquine, halofantrine, and quinine are linked. 13,14 We found that the IC 50 of field isolates for halofantrine usually increased as the parasites become more resistant to mefloquine.…”

Section: Discussionmentioning

confidence: 99%

“…5 The copy number of pfmdr1 was compared with that of the circumsporozoite gene, which occurs in a single copy in the genome. 14 …”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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

Chaiyaroj

Buranakiti²,

Angkasekwinai³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

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...

show abstract

mentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Chaiyaroj

Buranakiti²,

Angkasekwinai³

et al. 1999

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

show abstract

“…The results of several studies, mostly involving laboratory-adapted P. falciparum strains that were subjected to in vitro drug pressure, have suggested that amplification of pfmdr1 may be associated with resistance to chloroquine and/or amino alcohol drugs. [7][8][9][10][11][12] In some studies, however, the copy number of the pfmdr1 gene and in vitro drug resistance were not associated. 13,14 In addition to gene amplification, the pfmdr1 gene is known to undergo mutations leading to the substitution of amino acids at five distinct positions: 86, 184, 1034, 1042, and 1246.…”

Section: Introductionmentioning

confidence: 97%

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

Basco¹,

Ringwald²

2002

The American Journal of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

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.

show abstract

“…En P. falciparum los genes mdr se denominan pfmdr1 y, pfmdr2 (39,59,60,74) y se asocian con resistencia a cloroquina, mefloquina, halofantrina y quinina (47,48,(75)(76)(77)(78)(79). Los genes mdr de T. cruzi se conocen con los nombres tcpgp1, tcpgp2 (38,59) y en T. brucei spp.…”

Section: Papel De Los Genes Pgp Asociados Con El Fenotipo Mdr En La Munclassified

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

et al. 2005

View full text Add to dashboard Cite

Actualmente, los parásitos protozoarios son uno de los principales agentes causantes de morbilidad y mortalidad en el mundo, un problema complicado, además, por la aparición de resistencia a medicamentos en estos organismos. La resistencia a medicamentos observada en parásitos protozoarios se debe a diferentes mecanismos como la disminución de la entrada del medicamento a la célula por cambios en el transportador requerido, la pérdida de la activación del medicamento por parte del hospedero, las alteraciones en el blanco del medicamento y la expresión exagerada del transportador múltiple de medicamentos o glicoproteína P (Pgp). En esta revisión, nos centramos en: 1) el papel de las glicoproteínas P (Pgp) de la familia de proteínas ABC (ATP binding cassette) como los transportadores de múltiples medicamentos en la mediación de resistencia en protozoarios, especialmente en Leishmania, y en el desarrollo de resistencia cruzada para medicamentos estructural y funcionalmente no relacionados, y 2) en algunos conceptos relacionados con los mecanismos moduladores que podrían revertir la resistencia a medicamentos por fármacos y productos naturales. Numerosos moduladores o quimiosensibilizadores son conocidos por alterar la capacidad de las glicoproteínas P para mantener concentraciones intracelulares subtóxicas del medicamento; algunos ejemplos incluyen los bloqueadores de los canales de calcio como el verapamilo; sin embargo, se requieren altas concentraciones para una inhibición eficiente y duradera, las cuales producen efectos adversos indeseables. Por tanto, se necesitan más investigaciones relacionadas con los moduladores naturales para Pgp, los cuales podrían presentar menor toxicidad para el hospedero.Palabras clave: Leishmania, protozoos, multirresistencia, glicoproteína P, productos naturales. Leishmania: role of P glycoprotein in drug resistance and reversion strategiesProtozoan parasites are important causative agents of morbidity and mortality throughout the world -a problem further complicated by the emergence of drug resistance in these parasites. Mechanisms of drug resistance include the following: decreased uptake of the drug into the cell, loss of drug activation, alterations in the drug target, and over-expression of a well-known multiple drug transporter proteins. In this review, two critical components of resistance are stressed: (1) the role of ATP binding cassette proteins, such as P-glycoproteins, in mediating drug resistance in Leishmania and other protozoans, followed by development of cross-resistance to many structurally and functionally unrelated drugs, and (2) some concepts concerning the reversal mechanism of multidrug resistance by drugs and natural products. Several modulators or chemosensitizers alter the capacity of P-glycoproteins to maintain subtoxic intracellular drug concentrations. Calcium channel blockers such as verapamil act in this mode; however, high concentrations are required for an efficient and effective inhibition and, in addition, produce undesirable side effects. The di...

show abstract

Amplification of pfmdr1 associated with mefloquine and halofantrine resistance in Plasmodium falciparum from Thailand

Cited by 255 publications

References 23 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.

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

Leishmania: papel de la glicoproteína P en la mediación de resistencia a medicamentos y estrategias de reversión.

Contact Info

Product

Resources

About