Artemisinins and the biological basis for the PfATP6/SERCA hypothesis

Krishna, Sanjeev; Pulcini, Serena; Fatih, Farrah A.; Staines, Henry M.

doi:10.1016/j.pt.2010.06.014

Cited by 59 publications

(42 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The mode of action of endoperoxides is thought to require hememediated activation of the endoperoxide bridge, generating cytotoxic metabolites that cause oxidative damage to the cell (34,35). An alternative hypothesis that has been suggested is that endoperoxides interfere with calcium homeostasis within the parasite by a direct interaction with PfATP6 (36). When mature, gametocytes of both sexes have metabolized the erythrocyte hemoglobin, which is the likely causative agent underpinning the high sensitivity of asexual and early gametocytes to endoperoxides.…”

Section: Discussionmentioning

confidence: 99%

Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs

Delves

Ruecker

Straschil

et al. 2013

Antimicrob Agents Chemother

175

217

View full text Add to dashboard Cite

It is the mature gametocytes of Plasmodium that are solely responsible for parasite transmission from the mammalian host to the mosquito. They are therefore a logical target for transmission-blocking antimalarial interventions, which aim to break the cycle of reinfection and reduce the prevalence of malaria cases. Gametocytes, however, are not a homogeneous cell population. They are sexually dimorphic, and both males and females are required for parasite transmission. Using two bioassays, we explored the effects of 20 antimalarials on the functional viability of both male and female mature gametocytes of Plasmodium falciparum. We show that mature male gametocytes (as reported by their ability to produce male gametes, i.e., to exflagellate) are sensitive to antifolates, some endoperoxides, methylene blue, and thiostrepton, with submicromolar 50% inhibitory concentrations (IC 50 s), whereas female gametocytes (as reported by their ability to activate and form gametes expressing the marker Pfs25) are much less sensitive to antimalarial intervention, with only methylene blue and thiostrepton showing any significant activity. These findings show firstly that the antimalarial responses of male and female gametocytes differ and secondly that the mature male gametocyte should be considered a more vulnerable target than the female gametocyte for transmission-blocking drugs. Given the female-biased sex ratio of Plasmodium falciparum (ϳ3 to 5 females:1 male), current gametocyte assays without a sexspecific readout are unlikely to identify male-targeted compounds and prioritize them for further development. Both assays reported here are being scaled up to at least medium throughput and will permit identification of key transmission-blocking molecules that have been overlooked by other screening campaigns. Malaria is a disease of devastating economic and health burdens, with 216 million cases and 655,000 fatalities per year, among which most are either pregnant women or children of less than 5 years of age (1). The recent appreciation that local elimination and global eradication of malaria will require interventions that prevent parasite transmission from the human host to the vector (2) has revitalized the search for transmission-blocking drugs (3-7). One target of such drugs is the gametocyte, which is the parasite stage uniquely responsible for Plasmodium transmission to the mosquito.Plasmodium asexual parasites form gametocytes at a low frequency (0.2 to 1%) (8), with sexually committed merozoites from one precommitted schizont all forming gametocytes of the same sex (9). In Plasmodium falciparum, gametocytes develop over a period of 12 days, during which they are initially susceptible to schizonticidal antimalarials (stages I to III), but for the final part of their maturation process (stages IV and V), they become broadly insensitive to most antimalarial drugs, except for primaquine and methylene blue (6, 10-13). Mature stage V gametocytes, when considered as a single population, are developmentally arrested, and curr...

show abstract

Section: Discussionmentioning

confidence: 99%

Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs

Delves

Ruecker

Straschil

et al. 2013

Antimicrob Agents Chemother

175

217

View full text Add to dashboard Cite

show abstract

“…One of the hypotheses is based on the specific inhibition of P. falciparum ATPase 6 (PfATP6), an orthologue gene product of the mammal sarco-endoplasmic reticulum calciumdependent ATPase (SERCA). 3 Initial laboratory studies have suggested that L263E substitution in PfATP6 affects the active site and induces conformational changes, reducing the affinity between the enzyme and artemisinin. 4 Subsequent studies carried out on field isolates have shown an association between increased 50% inhibitory concentration (IC 50 ) for artemether and either a single amino acid substitution S769N (in South American strains) or double amino acid substitutions E431K and A623E (in African strains).…”

Section: Introductionmentioning

confidence: 99%

Molecular Epidemiology of Malaria in Cameroon. XXX. Sequence Analysis of Plasmodium falciparum ATPase 6, Dihydrofolate Reductase, and Dihydropteroate Synthase Resistance Markers in Clinical Isolates from Children Treated with an Artesunate-Sulfadoxine-Pyrimethamine Combination

Menemedengue

Sahnouni²,

Basco³

et al. 2011

The American Society of Tropical Medicine and Hygiene

View full text Add to dashboard Cite

Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes are reliable molecular markers for antifolate resistance. The P. falciparum ATPase 6 (pfatp6) gene has been proposed to be a potential marker for artemisinin resistance. In our previous clinical study, we showed that artesunate-sulfadoxine-pyrimethamine is highly effective against uncomplicated malaria in Yaoundé, Cameroon. In the present study, dhfr, dhps, and pfatp6 mutations in P. falciparum isolates obtained from children treated with artesunate-sulfadoxine-pyrimethamine were determined. All 61 isolates had wild-type Pfatp6 263, 623, and 769 alleles, and 11 (18%) had a single E431K substitution. Three additional mutations, E643Q, E432K, and E641Q, were detected. The results did not indicate any warning signal of serious concern (i.e., no parasites were seen with quintuple dhfr-dhps, DHFR Ile164Leu, or pfatp6 mutations), as confirmed by the high clinical efficacy of artesunate-sulfadoxine-pyrimethamine. Further studies are required to identify a molecular marker that reliably predicts artemisinin resistance.

show abstract

“…Other studies point to metal-independent activation of artemisinins (9). An alternative hypothesis is that artemisinin exerts its activity by directly inhibiting a single target, the calcium ATPase (PfATP6), in a manner that is heme independent and analogous to the inhibition of the sarco/endoplasmic reticulum Ca 2þ -ATPase by thapsigargin (10,11).…”

mentioning

confidence: 99%

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Klonis

Crespo-Ortiz²,

Bottová³

et al. 2011

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

321

314

View full text Add to dashboard Cite

Combination regimens that include artemisinin derivatives are recommended as first line antimalarials in most countries where malaria is endemic. However, the mechanism of action of artemisinin is not fully understood and the usefulness of this drug class is threatened by reports of decreased parasite sensitivity. We treated Plasmodium falciparum for periods of a few hours to mimic clinical exposure to the short half-life artemisinins. We found that drug treatment retards parasite growth and inhibits uptake of hemoglobin, even at sublethal concentrations. We show that potent artemisinin activity is dependent on hemoglobin digestion by the parasite. Inhibition of hemoglobinase activity with cysteine protease inhibitors, knockout of the cysteine protease falcipain-2 by gene deletion, or direct deprivation of host cell lysate, significantly decreases artemisinin sensitivity. Hemoglobin digestion is also required for artemisinin-induced exacerbation of oxidative stress in the parasite cytoplasm. Arrest of hemoglobin digestion by early stage parasites provides a mechanism for surviving short-term artemisinin exposure. These insights will help in the design of new drugs and new treatment strategies to circumvent drug resistance.erythrocyte | endoperoxide

show abstract

Artemisinins and the biological basis for the PfATP6/SERCA hypothesis

Cited by 59 publications

References 43 publications

Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs

Male and Female Plasmodium falciparum Mature Gametocytes Show Different Responses to Antimalarial Drugs

Molecular Epidemiology of Malaria in Cameroon. XXX. Sequence Analysis of Plasmodium falciparum ATPase 6, Dihydrofolate Reductase, and Dihydropteroate Synthase Resistance Markers in Clinical Isolates from Children Treated with an Artesunate-Sulfadoxine-Pyrimethamine Combination

Artemisinin activity againstPlasmodium falciparumrequires hemoglobin uptake and digestion

Contact Info

Product

Resources

About