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Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J, Wirjanata G, Sebayang BF, Price RN, Chatterjee A, Nagle A, Stasiak M, Charman SA, Angulo-Barturen I, Ferrer S, Belén Jiménez-Díaz M, Martínez MS, Gamo FJ, Avery VM, Ruecker A, Delves M, Kirk K, Berriman M, Kortagere S, Burrows J, Fan E, Bergman LW - Nat Commun (2014)

Bottom Line: Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds.A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites.Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.

ABSTRACT
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

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Related in: MedlinePlus

PA21A050 causes swelling of intraerythrocytic P. falciparum.Live cell images of trophozoite stages were obtained at 2 h from untreated and PA21A050-treated parasites attached to a glass-bottom Petri plate by a Nikon microscope equipped with an incubation chamber for regulating temperature and gas mixture. The diameter of the indicated number of parasites were measured from the images using the ImageJ software. Error bars indicate s.d.
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f5: PA21A050 causes swelling of intraerythrocytic P. falciparum.Live cell images of trophozoite stages were obtained at 2 h from untreated and PA21A050-treated parasites attached to a glass-bottom Petri plate by a Nikon microscope equipped with an incubation chamber for regulating temperature and gas mixture. The diameter of the indicated number of parasites were measured from the images using the ImageJ software. Error bars indicate s.d.

Mentions: We examined the effect of PA21A050 on P. falciparum development by time-lapse live cell imaging in erythrocytes starting from ring-stage parasites (Supplementary Movies 1 and 2). Ring-stage parasites progressed to develop into trophozoites while being exposed to PA21A050. At the late trophozoite stage there was visible increase in volume of the parasite, which was followed by dramatic apparent bursting; schizogony or merozoites were not observed (Supplementary Movie 2; notice swelling and bursting from 2,400 to 2,600 min time frames). These observations are consistent with the proposition that pyrazoleamides disrupt Na+ homeostasis, the effect of which becomes apparent coincident with the rise in [Na+] within the infected erythrocyte cytoplasm at the trophozoite stage. An increase in [Na+] in the parasite cytoplasm is predicted to give rise to an associated osmotic uptake of water and an associated swelling. To assess the extent of swelling, we measured the diameter of trophozoite-stage parasites in intact infected erythrocytes after 2 h of exposure to PA21A050 in still images of a number of parasites. As shown in Fig. 5, the average diameter of the treated trophozoite stage increased to 4.6 μm in 2 h compared with 2.5 μm in untreated control trophozoites from the same culture, consistent with the parasite having undergone significant swelling.


Pyrazoleamide compounds are potent antimalarials that target Na+ homeostasis in intraerythrocytic Plasmodium falciparum.

Vaidya AB, Morrisey JM, Zhang Z, Das S, Daly TM, Otto TD, Spillman NJ, Wyvratt M, Siegl P, Marfurt J, Wirjanata G, Sebayang BF, Price RN, Chatterjee A, Nagle A, Stasiak M, Charman SA, Angulo-Barturen I, Ferrer S, Belén Jiménez-Díaz M, Martínez MS, Gamo FJ, Avery VM, Ruecker A, Delves M, Kirk K, Berriman M, Kortagere S, Burrows J, Fan E, Bergman LW - Nat Commun (2014)

PA21A050 causes swelling of intraerythrocytic P. falciparum.Live cell images of trophozoite stages were obtained at 2 h from untreated and PA21A050-treated parasites attached to a glass-bottom Petri plate by a Nikon microscope equipped with an incubation chamber for regulating temperature and gas mixture. The diameter of the indicated number of parasites were measured from the images using the ImageJ software. Error bars indicate s.d.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263321&req=5

f5: PA21A050 causes swelling of intraerythrocytic P. falciparum.Live cell images of trophozoite stages were obtained at 2 h from untreated and PA21A050-treated parasites attached to a glass-bottom Petri plate by a Nikon microscope equipped with an incubation chamber for regulating temperature and gas mixture. The diameter of the indicated number of parasites were measured from the images using the ImageJ software. Error bars indicate s.d.
Mentions: We examined the effect of PA21A050 on P. falciparum development by time-lapse live cell imaging in erythrocytes starting from ring-stage parasites (Supplementary Movies 1 and 2). Ring-stage parasites progressed to develop into trophozoites while being exposed to PA21A050. At the late trophozoite stage there was visible increase in volume of the parasite, which was followed by dramatic apparent bursting; schizogony or merozoites were not observed (Supplementary Movie 2; notice swelling and bursting from 2,400 to 2,600 min time frames). These observations are consistent with the proposition that pyrazoleamides disrupt Na+ homeostasis, the effect of which becomes apparent coincident with the rise in [Na+] within the infected erythrocyte cytoplasm at the trophozoite stage. An increase in [Na+] in the parasite cytoplasm is predicted to give rise to an associated osmotic uptake of water and an associated swelling. To assess the extent of swelling, we measured the diameter of trophozoite-stage parasites in intact infected erythrocytes after 2 h of exposure to PA21A050 in still images of a number of parasites. As shown in Fig. 5, the average diameter of the treated trophozoite stage increased to 4.6 μm in 2 h compared with 2.5 μm in untreated control trophozoites from the same culture, consistent with the parasite having undergone significant swelling.

Bottom Line: Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds.A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites.Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Molecular Parasitology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 190129, USA.

ABSTRACT
The quest for new antimalarial drugs, especially those with novel modes of action, is essential in the face of emerging drug-resistant parasites. Here we describe a new chemical class of molecules, pyrazoleamides, with potent activity against human malaria parasites and showing remarkably rapid parasite clearance in an in vivo model. Investigations involving pyrazoleamide-resistant parasites, whole-genome sequencing and gene transfers reveal that mutations in two proteins, a calcium-dependent protein kinase (PfCDPK5) and a P-type cation-ATPase (PfATP4), are necessary to impart full resistance to these compounds. A pyrazoleamide compound causes a rapid disruption of Na(+) regulation in blood-stage Plasmodium falciparum parasites. Similar effect on Na(+) homeostasis was recently reported for spiroindolones, which are antimalarials of a chemical class quite distinct from pyrazoleamides. Our results reveal that disruption of Na(+) homeostasis in malaria parasites is a promising mode of antimalarial action mediated by at least two distinct chemical classes.

Show MeSH
Related in: MedlinePlus