Parasitic Diseases Commons^™

Mutation In The Plasmodium Falciparum Crt Protein Determines The Stereospecific Activity Of Antimalarial Cinchona Alkaloids, Carol E. Griffin, Jonathan M. Hoke, Upeka Samarakoon, Junhui Duan, Jianbing Mu, Michael T. Ferdig, David C. Warhurst, Roland Cooper

Collected Faculty Scholarship

The Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (-)-quinine and (+)-quinidine. The potency of (+)-isomers is greater than the (-)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility …

Does Anti-Malarial Drug Knowledge Predict Anti-Malarial Dispensing Practice In Drug Outlets? A Survey Of Medicine Retailers In Western Kenya., Andria Rusk, Nathan Smith, Diana Menya, Andrew Obala, Chrispinus Simiyu, Barasa Khwa-Otsyula, Wendy O'Meara

Collected Faculty Scholarship

Background

Malaria is a major cause of morbidity and mortality in Kenya, where it is the fifth leading cause of death in both children and adults. Effectively managing malaria is dependent upon appropriate treatment. In Kenya, between 17 to 83 percent of febrile individuals first seek treatment for febrile illness over the counter from medicine retailers. Understanding medicine retailer knowledge and behaviour in treating suspected malaria and dispensing anti-malarials is crucial.

Methods

To investigate medicine retailer knowledge about anti-malarials and their dispensing practices, a survey was conducted of all retail drug outlets that sell anti-malarial medications and serve residents of …

Chloroquine Susceptibility And Reversibility In A Plasmodium Falciparum Genetic Cross, Jigar J. Patel, Drew Thacker, Jon C. Tan, Perri Pleeter, Lisa Checkley, Joseph M. Gonzales, Bingbing Deng, Paul D. Roepe, Roland A. Cooper, Michael T. Ferdig

Collected Faculty Scholarship

Mutations in the Plasmodium falciparum chloroquine (CQ) resistance transporter (PfCRT), are major determinants of verapamil (VP)-reversible CQ resistance (CQR). In the presence of mutant PfCRT, additional genes contribute to the wide range of CQ susceptibilities observed. It is not known if these genes influence mechanisms of chemosensitization by CQR reversal agents. Using quantitative trait locus (QTL) mapping of progeny clones from the HB3 × Dd2 cross, we show that the P. falciparum multidrug resistance gene 1 (pfmdr1) interacts with the Southeast Asiaderived mutant pfcrt haplotype to modulate CQR levels. A novel chromosome 7 locus is predicted to contribute with the …

Accumulation Of Artemisinin Trioxane Derivatives Within Neutral Lipids Of Plasmodium Falciparum Malaria Parasites Is Endoperoxide-Dependent, Carmony L. Hartwig, Andrew S. Rosenthal, John D'Angelo, Carol E. Griffin, Gary H. Posner, Roland A. Cooper

Collected Faculty Scholarship

The antimalarial trioxanes, exemplified by the naturally occurring sesquiterpene lactone artemisinin and its semi-synthetic derivatives, contain an endoperoxide pharmacophore that lends tremendous potency against Plasmodium parasites. Despite decades of research, their mechanism of action remains unresolved. A leading model of anti-plasmodial activity hypothesizes that iron-mediated cleavage of the endoperoxide bridge generates cytotoxic drug metabolites capable of damaging cellular macromolecules. To probe the malarial targets of the endoperoxide drugs, we studied the distribution of fluorescent dansyl trioxane derivatives in living, intraerythrocytic-stage Plasmodium falciparum parasites using microscopic imaging. The fluorescent trioxanes rapidly accumulated in parasitized erythrocytes, localizing within digestive vacuole-associated neutral lipid …

Genome-Wide Compensatory Changes Accompany Drug Selected Mutations In The Plasmodium Falciparum Crt Gene, Hongying Jiang, Jigar J. Patel, Ming Yi, Jianbing Mu, Jinhui Ding, Robert Stephens, Roland Cooper, Michael T. Ferdig, Xin-Zhuan Su

Collected Faculty Scholarship

Mutations in PfCRT (Plasmodium falciparum chloroquine-resistant transporter), particularly the substitution at amino acid position 76, confer chloroquine (CQ) resistance in P. falciparum. Point mutations in the homolog of the mammalian multidrug resistance gene (pfmdr1) can also modulate the levels of CQ response. Moreover, parasites with the same pfcrt and pfmdr1 alleles exhibit a wide range of drug sensitivity, suggesting that additional genes contribute to levels of CQ resistance (CQR). Reemergence of CQ sensitive parasites after cessation of CQ use indicates that changes in PfCRT are deleterious to the parasite. Some CQR parasites, however, persist in the field and grow well …