Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y

Holmgren, Gabrielle; Gil, José Pedro; Ferreira, Pedro Eduardo; Veiga, Maria Isabel; Obonyo, Charles; Björkman, Anders

doi:10.1016/j.meegid.2005.09.001

Cited by 155 publications

(147 citation statements)

References 21 publications

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“…To date, several studies have demonstrated the association between resistance or decrease susceptibility to 4-amino-quinoline resistance and mutation in crt gene, changes in expression profiles and/or copy number variation in mdr1 gene ( Borges et al , 2011; Duraisingh & Cowman, 2005; Holmgren et al , 2006). Single nucleotide polymorphism (SNP) in Pfcrt (codon 76) is associated with CQ and AQ resistance in P. falciparum ( Ecker et al , 2012; Fidock et al , 2000; Ochong et al , 2003).…”

Section: Resultsmentioning

confidence: 99%

“…First, Plasmodium falciparum chloroquine resistance transporter ( Pfcrt ) Lys76Thr change is associated with CQ resistance and decreased sensitivity to AQ ( Ecker et al , 2012; Fidock et al , 2000; Ochong et al , 2003). Second, in the presence of Pfcrt Lys76Thr mutation, Plasmodium falciparum multidrug resistance gene 1 ( Pfmdr1 ), Asn86Tyr mutation enhances CQ resistance and decreases AQ sensitivity ( Cooper et al , 2005; Holmgren et al , 2006; Wellems, 2002). Currently, the mechanisms of AQ resistance are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

Ndung'u¹,

Langat²,

Magiri³

et al. 2017

Wellcome Open Res

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Background: The human malaria parasite Plasmodium falciparum has evolved complex drug evasion mechanisms to all available antimalarials. To date, the combination of amodiaquine-artesunate is among the drug of choice for treatment of uncomplicated malaria. In this combination, a short acting, artesunate is partnered with long acting, amodiaquine for which resistance may emerge rapidly especially in high transmission settings. Here, we used a rodent malaria parasite Plasmodium berghei ANKA as a surrogate of P. falciparum to investigate the mechanisms of amodiaquine resistance. Methods: We used serial technique to select amodiaquine resistance by submitting the parasites to continuous amodiaquine pressure. We then employed the 4-Day Suppressive Test to monitor emergence of resistance and determine the cross-resistance profiles. Finally, we genotyped the resistant parasite by PCR amplification, sequencing and relative quantitation of mRNA transcript of targeted genes. Results: Submission of P. berghei ANKA to amodiaquine pressure yielded resistant parasite within thirty-six passages. The effective dosage that reduced 90% of parasitaemia (ED 90) of sensitive line and resistant line were 4.29mg/kg and 19.13mg/kg, respectively. After freezing at -80ºC for one month, the resistant parasite remained stable with an ED 90 of 18.22mg/kg. Amodiaquine resistant parasites are also resistant to chloroquine (6fold), artemether (10fold), primaquine (5fold), piperaquine (2fold) and lumefantrine (3fold). Sequence analysis of Plasmodium berghei chloroquine resistant transporter revealed His95Pro mutation. No variation was identified in Plasmodium berghei multidrug resistance gene-1 (Pbmdr1), Plasmodium berghei deubiquitinating enzyme-1 or Plasmodium berghei Kelch13 domain nucleotide sequences. Amodiaquine resistance is also accompanied by high mRNA transcripts of key transporters; Pbmdr1, V-type/H+ pumping pyrophosphatase-2 and sodium hydrogen ion exchanger-1 and Ca 2+/H + antiporter. Conclusions: Selection of amodiaquine resistance yielded stable “multidrug-resistant’’ parasites and thus may be used to study common resistance mechanisms associated with other antimalarial drugs. Genome wide studies may elucidate other functionally important genes controlling AQ resistance in P. berghei.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

Ndung'u¹,

Langat²,

Magiri³

et al. 2017

Wellcome Open Res

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“…En conclusión, la gran prevalencia en nuestro estudio del alelo Asn 86, tanto en casos de respuesta adecuada como de falla al tratamiento, no nos permite afirmar que la presencia del alelo se relacione con uno u otro evento, como lo informan diversos autores (6,32,36,37). Con respecto a la distribución geográfica de alguno de los polimorfismos, podemos afirmar que, a diferencia de lo reportado en África y Asia, el alelo silvestre es mucho más frecuente en nuestras poblaciones de P. falciparum.…”

Section: Tratamientounclassified

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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“…Although response to AQ monotherapy was positive in early 2000 (Sowunmi et al 2001), recent reports suggest resistance to AQ monotherapy is increasing (Happi et al 2006) and is conferred by the same mutations in the parasite that confer resistance to CQ (Ochong et al 2003, Happi et al 2006, Holmgren et al 2006. Our results after evaluating recrudescent infections in 615 children enrolled in AQ efficacy studies over a seven-year period in an endemic area of malaria showed that AQ resistance is at 4%, a figure that is likely to rise as the use of the drug as monotherapy continues.…”

Section: Discussionmentioning

confidence: 99%

“…Recent suggestions have been made that in Africa mutant alleles of Pfcrt and Pfmdr-1 associated with CQ-resistance in P. falciparum are also associated with resistance to AQ (Ochong et al 2003, Happi et al 2006, Holmgren et al 2006. However, it is unclear if resistance to AQ also confers survival and propagation advantages to the parasite.…”

mentioning

confidence: 99%

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children

Sowunmi

Balogun

Gbotosho

et al. 2008

Mem. Inst. Oswaldo Cruz

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Characteristics of primary and recrudescent Plasmodium falciparum infections were evaluated in 25 children who did not recover after amodiaquine (AQ) treatment. Recrudescence was detected by a thick blood smear and confirmed by polymerase chain reaction. Over half of recrudescent events occurred after 14 days of initiation of treatment and were associated with relatively low asexual parasitaemia. We examined the gametocyte sex ratio (GSR) in these children and in age and gender-matched controls that had AQ-sensitive (AQ-S) infections (n = 50). In both AQ-S and AQ-resistant (AQ-R) infections, the GSR was female-biased pre-treatment and became male-biased

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Amodiaquine resistant Plasmodium falciparum malaria in vivo is associated with selection of pfcrt 76T and pfmdr1 86Y

Cited by 155 publications

References 21 publications

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

Amodiaquine resistance in Plasmodium berghei is associated with PbCRT His95Pro mutation, loss of chloroquine, artemisinin and primaquine sensitivity, and high transcript levels of key transporters

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

Some features of primary and recrudescent amodiaquine-resistant Plasmodium falciparum infections in Nigerian children

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