Medicine and Health Sciences Commons^™

Can Repurposing Drugs Play A Role In Malaria Control?, Roland A. Cooper, Laura Kirkman

Natural Sciences and Mathematics | Faculty Scholarship

Innovative drug treatments for malaria, optimally with novel targets, are needed to combat the threat of parasite drug resistance. As drug development efforts continue, there may be a role for a host-targeting, repurposed cancer drug administered together with an artemisinin combination therapy that was shown to improve the speed of recovery from a malaria infection.

Associations Between Varied Susceptibilities To Pfatp4 Inhibitors And Genotypes In Ugandan Plasmodium Falciparum Isolates., Oriana Kreutzfeld, Stephanie A. Rasmussen, Aarti A. Ramanathan, Patrick K. Tumwebaze, Oswald Byaruhanga, Thomas Katairo, Victor Asua, Martin Okitwi, Stephen Orena, Jennifer Legac, Melissa D. Conrad, Samuel L. Nsobya, Ozkan Aydemir, Jeffrey Bailey, Maelle Duffey, Brett R. Bayles, Akhil B. Vaidya, Roland A. Cooper, Philip J. Rosenthal

Natural Sciences and Mathematics | Faculty Scholarship

Among novel compounds under recent investigation as potential new antimalarial drugs are three independently developed inhibitors of the Plasmodium falciparum P-type ATPase (PfATP4): KAE609 (cipargamin), PA92, and SJ733. We assessed ex vivo susceptibilities to these compounds of 374 fresh P. falciparum isolates collected in Tororo and Busia districts, Uganda, from 2016 to 2019. Median IC50s were 65 nM for SJ733, 9.1 nM for PA92, and 0.5 nM for KAE609. Sequencing of pfatp4 for 218 of these isolates demonstrated many nonsynonymous single nucleotide polymorphisms; the most frequent mutations were G1128R (69% of isolates mixed or mutant), Q1081K/R (68%), G223S (25%), N1045K …

Drug Susceptibility Of Plasmodium Falciparum In Eastern Uganda: A Longitudinal Phenotypic And Genotypic Study, Patrick K. Tumwebaze, Thomas Katairo, Martin Okitwi, Oswald Byaruhanga, Stephen Orena, Victor Asua, Marvin Duvalsaint, Jennifer Legac, Sevil Chelebieva, Frida G. Ceja, Stephanie A. Rasmussen, Melissa D. Conrad, Samuel L. Nsobya, Ozkan Aydemir, Jeffrey A. Bailey, Brett R. Bayles, Philip J. Rosenthal, Roland A. Cooper

Natural Sciences and Mathematics | Faculty Scholarship

Background: Treatment and control of malaria depends on artemisinin-based combination therapies (ACTs) and is challenged by drug resistance, but thus far resistance to artemisinins and partner drugs has primarily occurred in southeast Asia. The aim of this study was to characterise antimalarial drug susceptibility of Plasmodium falciparum isolates from Tororo and Busia districts in Uganda.

Methods: In this prospective longitudinal study, P falciparum isolates were collected from patients aged 6 months or older presenting at the Tororo District Hospital (Tororo district, a site with relatively low malaria incidence) or Masafu General Hospital (Busia district, a high-incidence site) in eastern Uganda …

The Antimalarial Mmv688533 Provides Potential For Single-Dose Cures With A High Barrier To, James M. Murithi, Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, Tomas Yeo, Sachel Mok, Sylvie Klieber, Paul Desert, María Belén Jiménez-Díaz, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Sergio Wittlin, Anne-Catrin Uhlemann, Ric N. Price, Grennady Wirjanata, Rintis Noviyanti, Patrick K. Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco-Javier Gamo, Jayan Joseph, Shivendra Singh, Sridevi Bashyam, Jean Michel Augereau, Elie Giraud, Tanguy Bozec, Thierry Vermat, Gilles Tuffal, Jean-Michel Guillon, Jérôme Menegotto, Laurent Sallé, Guillaume Louit, Marie-José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Iñigo Angulo-Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C. Niles, Benjamin Blasco, Simon Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy

Natural Sciences and Mathematics | Faculty Scholarship

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in …

The Antimalarial Mmv688533 Provides Potential For Single-Dose Cures With A High Barrier To, James M. Murithi, Cécile Pascal, Jade Bath, Xavier Boulenc, Nina F. Gnädig, Charisse Flerida A. Pasaje, Kelly Rubiano, Tomas Yeo, Sachel Mok, Sylvie Klieber, Paul Desert, María Belén Jiménez-Díaz, Jutta Marfurt, Mélanie Rouillier, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Sergio Wittlin, Anne-Catrin Uhlemann, Ric N. Price, Grennady Wirjanata, Rintis Noviyanti, Patrick Tumwebaze, Roland A. Cooper, Philip J. Rosenthal, Laura M. Sanz, Francisco-Javier Gamo, Jayan Joseph, Shivendra Singh, Sridevi Bashyam, Jean Michel Augereau, Elie Giraud, Tanguy Bozec, Thierry Vermat, Gilles Tuffal, Jean-Michel Guillon, Jérôme Menegotto, Laurent Sallé, Guillaume Louit, Marie-José Cabanis, Marie Françoise Nicolas, Michel Doubovetzky, Rita Merino, Nadir Bessila, Iñigo Angulo-Barturen, Delphine Baud, Lidiya Bebrevska, Fanny Escudié, Jacquin C. Niles, Benjamin Blasco, Simon Campbell, Gilles Courtemanche, Laurent Fraisse, Alain Pellet, David A. Fidock, Didier Leroy

Natural Sciences and Mathematics | Faculty Scholarship

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in …

Balanced Impacts Of Fitness And Drug Pressure On The Evolution Of Pfmdr1 Polymorphisms In Plasmodium Falciparum., Marvin Duvalsaint, Melissa D. Conrad, Stephen Tukwasibwe, Patrick K. Tumwebaze, Jennifer Legac, Roland A. Cooper, Philip J. Rosenthal

Natural Sciences and Mathematics | Faculty Scholarship

BACKGROUND: Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1.

METHODS: Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the …