Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal
Nov 2012
Artemether-Lumefantrine Selects For Malaria Parasites With Decreased Lumefantrine Sensitivity Although Parasites Remain Sensitive To This Regimen In Tororo, Uganda, P. Tumwebaze, J. Bloome, O. Byaruhanga, C. Nakazibwe, A. Walakira, J. Okiring, S. L. Nsobya, Roland A. Cooper, P. J. Rosenthal
Roland A. Cooper
Artemisinin-based combination therapies (ACTs) may select for malaria parasites with decreased drug sensitivity. We studied the sensitivity of parasites from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to February, 2012. When Plasmodium falciparum malaria was diagnosed, blood was obtained, parasites (286 isolates) were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), or piperaquine (PQ) for 72 h, and ex vivo sensitivities were assessed by HRP-2-based ELISA. Sensitivities (nM) to CQ (median IC50 486.2; IQR 206.5-748.8), AQ (83.3; 58.4-132.4), PQ (20.3; 7.6-47.5) and QN (126.4; 74.9-196.3) varied widely; …
Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal
Nov 2011
Ex Vivo Drug Sensitivity Of Malaria Parasites Under Selective Pressure In Tororo, Uganda, P. K. Tumebaze, O. Byaruhanga, J. Okiring, S. L. Nsobya, R. A. Cooper, P. J. Rosenthal
Roland A. Cooper
Artemisinin-based combination therapies (ACTs) are standard treatments for uncomplicated malaria in Africa. ACTs provide highly effective treatment, and regular use may offer protection against malaria in high risk populations. However, increased use of ACTs may select for parasites with decreased sensitivity. We studied the ex vivo sensitivity of malaria parasites collected from children enrolled in treatment and prevention trials in Tororo, Uganda from June, 2010 to August, 2011. When P. falciparum malaria was diagnosed, blood was obtained, parasites were cultured with serial dilutions of chloroquine (CQ), monodesethylamodiaquine (AQ), quinine (QN), dihydroartemisinin (DHA), lumefantrine (LM), and piperaquine (PQ) for 72 hours, …
Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems
Nov 2005
Pfcg2, A Plasmodium Falciparum Protein Peripherally Associated With The Parasitophorous Vacuolar Membrane, Is Expressed In The Period Of Maximum Hemoglobin Uptake And Digestion By Trophozoites, Roland A. Cooper, Janni Papakrivos, Kristen D. Lane, Hisashi Fujioka, Klaus Lingelbach, Thomas E. Wellems
Roland A. Cooper
A Plasmodium falciparum gene closely linked to the chloroquine resistance locus encodes PfCG2, a predicted 320-330kDa protein. In the parasitized erythrocyte, PfCG2 expression rises sharply in the trophozoite stage and is detected in electron-dense patches along the parasitophorous vacuolar membrane (PVM), in the cytoplasm and in the digestive vacuole (DV). Results of extraction and partitioning experiments show that PfCG2 is a peripheral membrane protein. Exposure of trophozoite-infected erythrocytes to trypsin-containing buffer after streptolysin O permeabilization indicates that PfCG2 is exposed to the erythrocyte cytosol at the outer face of the PVM. PfCG2 is highly susceptible to hydrolysis by aspartic and …
Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig
May 2005
Pfcrt Is More Than The Plasmodium Falciparum Chloroquine Resistance Gene: A Functional And Evolutionary Perspective, Roland A. Cooper, Carmony L. Hartwig, Michael T. Ferdig
Roland A. Cooper
Genetic, physiological and pharmacological studies are gradually revealing the molecular basis of chloroquine resistance (CQR) in the malaria parasite, Plasmodium falciparum. Recent highlights include the discovery of a key gene associated with resistance, pfcrt (Plasmodium falciparum chloroquine resistance transporter; PfCRT), encoding a novel transporter, and the characterization of global selective sweeps of haplotypes containing a K76T amino acid change within this protein. Little is known about the cellular mechanism by which resistant parasites escape the effects of chloroquine (CQ), one of the most promising drugs ever deployed, due in part to an unresolved mechanism of action. The worldwide spread of …
Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci
Feb 2004
Proteomic Approaches To Studying Drug Targets And Resistance In Plasmodium, R. A. Cooper, D. J. Carucci
Roland A. Cooper
Ever increasing drug resistance by Plasmodium falciparum, the most virulent of human malaria parasites, is creating new challenges in malaria chemotherapy. The entire genome sequences of P. falciparum and the rodent malaria parasite, P. yoelii yoelii are now available. Extensive genome sequence data from other Plasmodium species including another important human malaria parasite, P. vivax are also available. Powerful research techniques coupled to genomic resources are needed to help identify new drug and vaccine targets against malaria. Applied to Plasmodium, proteomics combines high-resolution protein or peptide separation with mass spectrometry and computer software to rapidly identify large numbers of proteins …
Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li
Jul 2003
Plasmepsin 4, The Food Vacuole Aspartic Proteinase Found In All Plasmodium Spp. Infecting Man, John B. Dame, Charles A. Yowell, Levi Omara-Opyene, Jane M. Carlton, Roland A. Cooper, Tang Li
Roland A. Cooper
Plasmepsins are aspartic proteinases of the malaria parasite, and seven groups of plasmepsins have been identified by comparing genomic sequence data available for the genes encoding these enzymes from Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium berghei, and Plasmodium yoelii. The food vacuole plasmepsins typified by plasmepsin 4 from P. falciparum (PfPM4) constitute one of these groups. Genes encoding the ortholog of PfPM4 have been cloned from Plasmodium ovale, Plasmodium malariae, and P. vivax. In addition, P. falciparum contains three paralagous food vacuole plasmepsins or plasmepsin-like enzymes that appear to have arisen by gene duplication, plasmepsins 1 (PfPM1), 2 (PfPM2) …
