Mechanisms of Resistance of Malaria Parasites to Antifolates

Gregson, Aric L.; Plowe, Christopher V.

doi:10.1124/pr.57.1.4

Cited by 416 publications

(392 citation statements)

References 277 publications

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“…In Plasmodium spp., blocking of folate synthesis by antifolates results in decreased concentrations of tetrahydrofolate, decreased conversion of serine to glycine, reduced synthesis of thymidylate, and ultimately to decreased production of parasite DNA (Gregson & Plowe, 2005). Rapidly dividing cells, such as Plasmodium parasites, have a high demand for nucleotide precursors for DNA synthesis, and thus are particularly sensitive to antifolates.…”

Section: Folate and Antifolate Metabolism In Plasmodium Parasitesmentioning

confidence: 99%

“…Rapidly dividing cells, such as Plasmodium parasites, have a high demand for nucleotide precursors for DNA synthesis, and thus are particularly sensitive to antifolates. DHPS and DHFR inhibitors act against all human malaria parasites, but P. falciparum is inherently more sensitive than P. vivax , P. malariae and P. ovale (Gregson & Plowe, 2005). …”

Section: Folate and Antifolate Metabolism In Plasmodium Parasitesmentioning

confidence: 99%

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Safety and benefits of interventions to increase folate status in malaria‐endemic areas

et al. 2017

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SummaryFor decades, folic acid has routinely been given to prevent or treat anaemia in children, pregnant women and people with sickle cell disease. However, there is no conclusive evidence that folate deficiency anaemia constitutes a public health problem in any of these groups. Industrial flour fortification is recommended and implemented in many countries to combat neural tube defects. Dietary folates or folic acid can antagonise the action of antifolate drugs that play a critical role in the prevention and treatment of malaria. Randomised trials have shown that folic acid supplementation increases the rate of treatment failures with sulfadoxine‐pyrimethamine. The efficacy of antifolate drugs against Plasmodium is maximized in the absence of exogenous folic acid, suggesting that there is no safe minimum dose of ingested folic acid. We here review the safety and benefits of interventions to increase folate status in malaria‐endemic countries. We conclude that formal cost‐benefit analyses are required.

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Section: Folate and Antifolate Metabolism In Plasmodium Parasitesmentioning

confidence: 99%

Section: Folate and Antifolate Metabolism In Plasmodium Parasitesmentioning

confidence: 99%

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

et al. 2017

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“…Pyrimethamine and sulfadoxine target the parasite proteins DHFR and DHPS, respectively, and increasing resistance is conferred by ordered accumulating point mutations, of which DHPS codon 581 is one of the final to occur (7). The mutation at DHPS codon 581 has been associated with high-level in vitro resistance (8), as well as treatment failure in children (9,10).…”

mentioning

confidence: 99%

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment

Harrington

Mutabingwa

Muehlenbachs

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

188

244

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Intermittent preventive treatment in pregnancy (IPTp) is used to prevent Plasmodium falciparum malaria. However, parasites resistant to the IPTp drug sulfadoxine-pyrimethamine (SP) have emerged worldwide, and infections with mixed resistant and susceptible parasites are exacerbated by pyrimethamine in mice. In a prospective delivery cohort in Muheza, Tanzania, we examined the effects of SP IPTp on parasite resistance alleles, parasite diversity, level of parasitemia, and inflammation in the placenta. IPTp use was associated with an increased fraction of parasites carrying the resistance allele at DHPS codon 581, an increase in the level of parasitemia, and more intense placental inflammation. The lowest mean level of parasite diversity and highest mean level of parasitemia occurred in women after recent IPTp use. These findings support a model of parasite release and facilitation, whereby the most highly resistant parasites out-compete less fit parasite populations and overgrow under drug pressure. Use of partially effective anti-malarial agents for IPTp may exacerbate malaria infections in the setting of widespread drug resistance.evolution of drug resistance ͉ intermittent preventive treatment in pregnancy ͉ malaria drug resistance ͉ pregnancy malaria M alaria during pregnancy causes both maternal and fetal morbidity and mortality, including the deaths of an estimated 100,000 infants each year because of malaria-related low birth weight. The World Health Organization recommends that women living in sub-Saharan Africa receive at least two doses of intermittent preventive treatment (IPTp) with sulfadoxinepyrimethamine (SP) to prevent malaria and improve pregnancy outcomes (1-5) and this advice is widely followed. However, the rapid spread of SP-resistant parasites might undermine the efficacy of SP-IPTp, although it still confers benefits in areas with low to moderate levels of drug resistance (6). The effect of SP IPTp in areas where resistant parasites are more widespread has not been studied.Pyrimethamine and sulfadoxine target the parasite proteins DHFR and DHPS, respectively, and increasing resistance is conferred by ordered accumulating point mutations, of which DHPS codon 581 is one of the final to occur (7). The mutation at DHPS codon 581 has been associated with high-level in vitro resistance (8), as well as treatment failure in children (9, 10). Single-dose treatment of children with SP has been associated with an increase in parasite resistance alleles (11, 12), but little work has been done to examine the relationship between IPTp and selection for drug resistance alleles. One recent study observed an increased prevalence of placental infections harboring the DHFR triple mutant in women who had received pyrimethamine prophylaxis during pregnancy, as compared with women who had not (13). In contrast, IPTp use was not related to increased prevalence of resistance alleles at the same study site (14). Modeling studies have proposed that IPTp is less likely to contribute to accumulating drug resistance as...

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“…that cause malaria. The evolution and worldwide spread of resistance to chloroquine (CQ) over the past 50 years (1) and the subsequent failure of sulfadoxinepyrimethamine (SP) (1,2) have created a crisis for many African nations and other malaria-endemic countries (3). A number of these countries have adopted the highly effective artemisinin-based combination therapies (ACTs) as their first-line therapy for uncomplicated malaria, but ACTs are not yet widely available.…”

mentioning

confidence: 99%

Benefits of using multiple first-line therapies against malaria

Boni

Smith

Laxminarayan

2008

Proc. Natl. Acad. Sci. U.S.A.

129

124

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Despite the availability of many drugs and therapies to treat malaria, many countries' national policies recommend using a single first-line therapy for most clinical malaria cases. To assess whether this is the best strategy for the population as a whole, we designed an evolutionary-epidemiological modeling framework for malaria and compared the benefits of different treatment strategies in the context of resistance evolution. Our results show that the population-wide use of multiple first-line therapies (MFT) against malaria yields a better clinical outcome than using a single therapy or a cycling strategy where therapies are rotated, either on a fixed cycling schedule or when resistance levels or treatment failure become too high. MFT strategies also delay the emergence and slow the fixation of resistant strains (phenotypes), and they allow a larger fraction of the population to be treated without trading off future treatment of cases that may be untreatable because of high resistance levels. Earlier papers have noted that cycling strategies have the disadvantage of creating a less temporally variable environment than MFT strategies, making resistance evolution easier for the parasite. Here, we illustrate a second feature of parasite ecology that impairs the performance of cycling policies, namely, that cycling policies degrade the mean fitness of the parasite population more quickly than MFT policies, making it easier for new resistant types to invade and spread. The clinical benefits of using multiple first-line therapies against malaria suggest that MFT policies should play a key role in malaria elimination and control programs. drug resistance ͉ epidemiology ͉ evolution ͉ treatment strategies ͉ cost of resistance

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Mechanisms of Resistance of Malaria Parasites to Antifolates

Cited by 416 publications

References 277 publications

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

Safety and benefits of interventions to increase folate status in malaria‐endemic areas

Competitive facilitation of drug-resistant Plasmodium falciparum malaria parasites in pregnant women who receive preventive treatment

Benefits of using multiple first-line therapies against malaria

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