Molecular Markers of Plasmodium Resistance to Antimalarials

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

doi:10.1007/978-3-0346-0480-2_13

Cited by 16 publications

(16 citation statements)

References 178 publications

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“…Multiple investigations have focused on pfmdr1 , which encodes an ATP-binding cassette (ABC) transporter resident on the digestive vacuole and can vary via point mutations or copy number [42]. Field studies and laboratory investigations demonstrate that pfmdr1 gene amplification is associated with an increased risk of parasite recrudescence following mefloquine or artesunate–mefloquine treatment, and in-vitro resistance to mefloquine accompanied by reduced susceptibility to ART [36,54,55].…”

Section: Recent Advances In Defining Artemisinin Mode Of Action and Mmentioning

confidence: 99%

“…Several parasite proteins have been implicated in decreased susceptibility to artemisinins (ARTs), including PfATP6 (proposed to be in the endoplasmic reticulum [41]), PfMDR1 on the digestive vacuole [42], PfMRP1 on the parasite plasma membrane [43], and UBP-1 whose ortholog in Plasmodium chabaudi is associated with ART resistance [44]. The digestive vacuole protein PfCRT is also indicated as mutations that confer chloroquine resistance have been shown to significantly increase susceptibility to ARTs [45].…”

Section: Figurementioning

confidence: 99%

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Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Henrich¹,

Passi²,

Fidock

2011

Current Opinion in Infectious Diseases

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115

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Purpose of review Artemisinin-based combination therapies (ACTs) have been deployed globally with remarkable success for more than 10 years without having lost their malaria treatment efficacy. However, recent reports from the Thai–Cambodian border reveal evidence of emerging resistance to artemisinins. The latest published clinical and molecular findings are summarized herein. Recent findings Clinical studies have identified delayed parasite clearance time as the most robust marker of artemisinin resistance. Resistance has only been documented from Southeast Asia and has been observed in isolates that show no significant decrease in drug susceptibility in vitro. Genetic investigations have yet to uncover robust molecular markers. In-vitro studies have identified parasite quiescence or dormancy mechanisms that protect early ‘ring-stage’ intra-erythrocytic parasites against short-term artemisinin exposure. This might be achieved by reducing the rate of hemoglobin degradation, important for artemisinin bioactivation. Summary Should ACTs fail, no suitable alternatives exist as first-line treatments of P. falciparum malaria. Intensified efforts are essential to monitor the spread of resistance, define therapeutic and operational strategies to counter its impact, and understand its molecular basis. Success in these areas is critical to ensuring that recent gains in reducing the burden of malaria are not lost.

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Section: Recent Advances In Defining Artemisinin Mode Of Action and Mmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Henrich¹,

Passi²,

Fidock

2011

Current Opinion in Infectious Diseases

Self Cite

115

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“…Dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS) are known targets of pyrimethamine and sulfadoxine, respectively [4]. These drugs specifically inhibit the enzymes of the folate pathway to kill the parasites.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, it has been reported that treatment with artemether-lumefantrine selects for the pfmdr1 wild-type N86 allele [8–10]. Pfmdr1 amplification resulting in multiple gene copies is associated with resistance to amino alcohols (mefloquine and lumefantrine) [4, 11]. Recent studies have demonstrated that mutations in Kelch propeller 13 is directly associated with artemisinin resistance [12].…”

Section: Introductionmentioning

confidence: 99%

Characterization of Plasmodium falciparum genes associated with drug resistance in Hodh Elgharbi, a malaria hotspot near Malian–Mauritanian border

Salem

Lekweiry

Bouchiba

et al. 2017

Malar J

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BackgroundA malaria hotspot in the southeastern region of Mauritania, near the Malian border, may hamper malaria control strategies. The objectives were to estimate the prevalence of genetic polymorphisms associated with drug resistance in Plasmodium falciparum isolates and establish baseline data.MethodsThe study was conducted in two malaria-endemic areas in Hodh Elgharbi, situated in the Malian–Mauritanian border area. Blood samples were collected from symptomatic patients. Single nucleotide polymorphisms in Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps were genotyped using PCR-restriction fragment length polymorphism, DNA sequencing and primer extension. The Pfmdr1 gene copy number was determined by real-time PCR.ResultsOf 280 P. falciparum-infected patients, 193 (68.9%) carried the Pfcrt 76T mutant allele. The Pfmdr1 86Y and 184F mutations were found in 61 (23.1%) of 264 isolates and 167 (67.6%) of 247 samples that were successfully genotyped, respectively. Pfmdr1 mutant alleles 1034C, 1042D and 1246Y were rarely observed. Of 102 P. falciparum isolates analysed, ten (9.8%) had more than one copy of Pfmdr1 gene. The prevalence of isolates harbouring at least triple mutant Pfdhfr 51I, 59R, 108 N/T was 42% (112/268), of which 42 (37.5%) had an additional Pfdhps 437G mutation. The Pfdhps 540E mutation was observed in four isolates (1.5%), including three associated with Pfdhfr triple mutant. Only two quintuple mutants (Pfdhfr-51I-59R-108N Pfdhps-437G-540E) were observed.ConclusionsThe observed mutations in Pfdhfr, Pfdhps, Pfmdr1, and Pfcrt may jeopardize the future of seasonal malaria chemoprevention based on amodiaquine-sulfadoxine-pyrimethamine, intermittent preventive treatment for pregnant women using sulfadoxine-pyrimethamine, and treatment with artesunate-amodiaquine. Complementary studies should be carried out to document the distribution, origin and circulation of P. falciparum populations in this region and more widely in the country to assess the risk of the spread of resistance.

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“…We also note that PND activity does not appear to be significantly influenced by variant alleles of pfcrt and pfmdr1, which are common to field isolates and which are known to be major determinants of parasite resistance to chloroquine and ADQ (62)(63)(64). These genes encode transporters present on the digestive vacuole membrane, where they appear to modulate drug accumulation in this acidic compartment and regulate drug access to heme (65,66).…”

Section: Figmentioning

confidence: 79%

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

Henrich

Saénz

Cremers

et al. 2014

Antimicrob Agents Chemother

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The increasing prevalence in Southeast Asia of Plasmodium falciparum infections with delayed parasite clearance rates, following treatment of malaria patients with the artemisinin derivative artesunate, highlights an urgent need to identify which of the currently available artemisinin-based combination therapies (ACTs) are most suitable to treat populations with emerging artemisinin resistance. Here, we demonstrate that the rodent Plasmodium berghei SANA strain has acquired artemisinin resistance following drug pressure, as defined by reduced parasite clearance and early recrudescence following daily exposure to high doses of artesunate or the active metabolite dihydroartemisinin. Using the SANA strain and the parental drug-sensitive N strain, we have interrogated the antimalarial activity of five ACTs, namely, artemether-lumefantrine, artesunate-amodiaquine, artesunatemefloquine, dihydroartemisinin-piperaquine, and the newest combination artesunate-pyronaridine. By monitoring parasitemia and outcome for 30 days following initiation of treatment, we found that infections with artemisinin-resistant P. berghei SANA parasites can be successfully treated with artesunate-pyronaridine used at doses that are curative for the parental drug-sensitive N strain. No other partner drug combination was as effective in resolving SANA infections. Of the five partner drugs tested, pyronaridine was also the most effective at suppressing the recrudescence of SANA parasites. These data support the potential benefit of implementing ACTs with pyronaridine in regions affected by artemisinin-resistant malaria.

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Molecular Markers of Plasmodium Resistance to Antimalarials

Cited by 16 publications

References 178 publications

Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Recent clinical and molecular insights into emerging artemisinin resistance in Plasmodium falciparum

Characterization of Plasmodium falciparum genes associated with drug resistance in Hodh Elgharbi, a malaria hotspot near Malian–Mauritanian border

Evidence for Pyronaridine as a Highly Effective Partner Drug for Treatment of Artemisinin-Resistant Malaria in a Rodent Model

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