PfCRT and its role in antimalarial drug resistance

Ecker, Andrea; Lehane, Adele M.; Clain, Jérôme; Fidock, David A.

doi:10.1016/j.pt.2012.08.002

Cited by 241 publications

(293 citation statements)

References 127 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). Recent studies also identified potential crt background mutations; Ile356Thr and Asn326Ser that associate with artemisinin resistance ( Miotto et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Mutation at positions 86, 184, 1034, 1042, and 1246 in Pfmdr1 mediate and/or modulate CQ, LM and mefloquine resistance ( Ecker et al , 2012; Price et al , 1999; Price et al , 2004; Sisowath et al , 2005). Studies in the rodent malaria Plasmodium chabaudi found no association between crt and CQ resistance ( Afonso et al , 2006; Hunt et al , 2004).…”

Section: Resultsmentioning

confidence: 99%

“…The 4-amino-quinoline resistance in Plasmodium falciparum resistance is strongly associated with polymorphisms in two key genes. 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).…”

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: Resultsmentioning

confidence: 99%

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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“…The activity of the 1,2,4-oxadiazole series mirrored that of chloroquine rather than that of the DHFR inhibitors pyrimethamine and cycloguanil, with a 60-fold or greater increase in activity against pfcrt wild-type strain HL1212 than pfcrt mutant HL1210 (Table 3). These results suggest that mutated PfCRT might play a direct role in P. falciparum resistance to the 1,2,4-oxadiazole series and, by extension, that the mode of action of these compounds could reside in the digestive vacuole, from which mutant forms of the PfCRT transmembrane transporter are postulated to exclude chloroquine in resistant parasites (32,33).…”

Section: Genotypic Validation Of Selected P Falciparum Strainsmentioning

confidence: 90%

Identification and Deconvolution of Cross-Resistance Signals from Antimalarial Compounds Using Multidrug-Resistant Plasmodium falciparum Strains

Chugh

Scheurer

Sax

et al. 2015

Antimicrob Agents Chemother

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h Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.

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“…In the case of AQ/SP, mediators of drug resistance are well characterized. For AQ, resistance is mediated principally by the 76T mutation in Plasmodium falciparum crt (pfcrt) (16)(17)(18), which encodes a putative drug transporter, and is augmented by polymorphisms in a second predicted transporter gene, pfmdr1. The pfmdr1 86Y and 1246Y mutations are common in Africa and mediate decreased sensitivity to AQ (16,(19)(20)(21); the Y184F allele is also highly polymorphic but is of uncertain significance.…”

mentioning

confidence: 99%

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

Somé

Zongo

Compaoré

et al. 2014

Antimicrob Agents Chemother

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e Seasonal malaria chemoprevention (SMC), with regular use of amodiaquine plus sulfadoxine-pyrimethamine (AQ/SP) during the transmission season, is now a standard malaria control measure in the Sahel subregion of Africa. Another strategy under study is SMC with dihydroartemisinin plus piperaquine (DP). Plasmodium falciparum single nucleotide polymorphisms (SNPs) in P. falciparum crt (pfcrt), pfmdr1, pfdhfr, and pfdhps are associated with decreased response to aminoquinoline and antifolate antimalarials and are selected by use of these drugs. To characterize selection by SMC of key polymorphisms, we assessed 13 SNPs in P. falciparum isolated from children aged 3 to 59 months living in southwestern Burkina Faso and randomized to receive monthly DP or AQ/SP for 3 months in 2009. We compared SNP prevalence before the onset of SMC and 1 month after the third treatment in P. falciparum PCR-positive samples from 120 randomly selected children from each treatment arm and an additional 120 randomly selected children from a control group that did not receive SMC. The prevalence of relevant mutations was increased after SMC with AQ/SP. Significant selection was seen for pfcrt 76T (68.5% to 83.0%, P ‫؍‬ 0.04), pfdhfr 59R (54.8% to 83.3%, P ‫؍‬ 0.0002), and pfdhfr 108N (55.0% to 87.2%, P ‫؍‬ 0.0001), with trends toward selection of pfmdr1 86Y, pfdhfr 51I, and pfdhps 437G. After SMC with DP, only borderline selection of wild-type pfmdr1 D1246 (mutant; 7.7% to 0%, P ‫؍‬ 0.05) was seen. In contrast to AQ/SP, SMC with DP did not clearly select for known resistance-mediating polymorphisms. SMC with AQ/ SP, but not DP, may hasten the development of resistance to components of this regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT00941785.)

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PfCRT and its role in antimalarial drug resistance

Cited by 241 publications

References 127 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

Identification and Deconvolution of Cross-Resistance Signals from Antimalarial Compounds Using Multidrug-Resistant Plasmodium falciparum Strains

Selection of Drug Resistance-Mediating Plasmodium falciparum Genetic Polymorphisms by Seasonal Malaria Chemoprevention in Burkina Faso

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