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Mechanisms of Resistance

Role of pfmdr1 Amplification and Expression in Induction of Resistance to Artemisinin Derivatives in Plasmodium falciparum

Marina Chavchich, Lucia Gerena, Jennifer Peters, Nanhua Chen, Qin Cheng, Dennis E. Kyle
Marina Chavchich
1Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Q4051
2Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Q4029, Australia
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Lucia Gerena
3Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910
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Jennifer Peters
1Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Q4051
2Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Q4029, Australia
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Nanhua Chen
1Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Q4051
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Qin Cheng
1Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Q4051
2Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston, Q4029, Australia
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Dennis E. Kyle
1Australian Army Malaria Institute, Weary Dunlop Drive, Gallipoli Barracks, Enoggera, Q4051
3Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910
4Department of Global Health, College of Public Health, University of South Florida, 3720 Spectrum Blvd., Tampa, Florida 33612
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  • For correspondence: dkyle@health.usf.edu
DOI: 10.1128/AAC.00947-09
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ABSTRACT

Artemisinin and its derivatives are the most rapidly acting and efficacious antimalarial drugs currently available. Although resistance to these drugs has not been documented, there is growing concern about the potential for resistance to develop. In this paper we report the selection of parasite resistance to artelinic acid (AL) and artemisinin (QHS) in vitro and the molecular changes that occurred during the selection. Exposure of three Plasmodium falciparum lines (W2, D6, and TM91C235) to AL resulted in decreases in parasite susceptibilities to AL and QHS, as well as to mefloquine, quinine, halofantrine, and lumefantrine. The changes in parasite susceptibility were accompanied by increases in the copy number, mRNA expression, and protein expression of the pfmdr1 gene in the resistant progenies of W2 and TM91C235 parasites but not in those of D6 parasites. No changes were detected in the coding sequences of the pfmdr1, pfcrt, pfatp6, pftctp, and pfubcth genes or in the expression levels of pfatp6 and pftctp. Our data demonstrate that P. falciparum lines have the capacity to develop resistance to artemisinin derivatives in vitro and that this resistance is achieved by multiple mechanisms, to include amplification and increased expression of pfmdr1, a mechanism that also confers resistance to mefloquine. This observation is of practical importance, because artemisinin drugs are often used in combination with mefloquine for the treatment of malaria.

  • Copyright © 2010 American Society for Microbiology
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Role of pfmdr1 Amplification and Expression in Induction of Resistance to Artemisinin Derivatives in Plasmodium falciparum
Marina Chavchich, Lucia Gerena, Jennifer Peters, Nanhua Chen, Qin Cheng, Dennis E. Kyle
Antimicrobial Agents and Chemotherapy May 2010, 54 (6) 2455-2464; DOI: 10.1128/AAC.00947-09

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Role of pfmdr1 Amplification and Expression in Induction of Resistance to Artemisinin Derivatives in Plasmodium falciparum
Marina Chavchich, Lucia Gerena, Jennifer Peters, Nanhua Chen, Qin Cheng, Dennis E. Kyle
Antimicrobial Agents and Chemotherapy May 2010, 54 (6) 2455-2464; DOI: 10.1128/AAC.00947-09
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KEYWORDS

antimalarials
artemisinins
drug resistance
Genes, Protozoan
Multidrug Resistance-Associated Proteins
Plasmodium falciparum

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