Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro

Chen, Nanhua, Chavchich, Marina, Peters, Jennifer M., Kyle, Dennis E., Gatton, Michelle L., & Cheng, Qin (2010) Deamplification of pfmdr1-Containing Amplicon on Chromosome 5 in Plasmodium falciparum Is Associated with Reduced Resistance to Artelinic Acid In Vitro. Antimicrobial Agents and Chemotherapy, 54(8), pp. 3395-3401.

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Amplification of the Plasmodium falciparum multidrug resistance 1 gene (pfmdr1) has been implicated in multidrug resistance, including in vitro resistance to artelinic acid (AL). The stability and fitness of having multiple copies of pfmdr1 are important factors due to their potential effects on the resistance phenotype of parasites. These factors were investigated by using an AL-resistant line of P. falciparum (W2AL80) and clones originating from W2AL80. A rapid reduction in pfmdr1 copy number (CN) was observed in the uncloned W2AL80 line; 63% of this population reverted to a CN of <3 without exposure to the drug. Deamplification of the pfmdr1 amplicon was then determined in three clones, each initially containing three copies of pfmdr1. Interestingly, two outcomes were observed during 3 months without drug pressure. In one clone, parasites with fewer than 3 copies of pfmdr1 emerged rapidly. In two other clones, the reversion was significantly delayed. In all subclones, the reduction in pfmdr1 CN involved the deamplification of the entire amplicon (19 genes). Importantly, deamplification of the pfmdr1 amplicon resulted in partial reversal of resistance to AL and increased susceptibility to mefloquine. These results demonstrate that multiple copies of the pfmdr1-containing amplicon in AL-resistant parasites are unstable when drug pressure is withdrawn and have practical implications for the maintenance and spread of parasites resistant to artemisinin derivatives.

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ID Code: 75116
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 6 months
Keywords: Plasmodium, falciparum, artelinic acid, pfmdr1, resistance
DOI: 10.1128/AAC.01421-09
ISSN: 1098-6596
Subjects: Australian and New Zealand Standard Research Classification > BIOLOGICAL SCIENCES (060000) > MICROBIOLOGY (060500) > Infectious Agents (060502)
Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > PUBLIC HEALTH AND HEALTH SERVICES (111700) > Public Health and Health Services not elsewhere classified (111799)
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Schools > School of Public Health & Social Work
  • NIH/RO1AI058973
  • NMHRC/496702
Deposited On: 25 Aug 2014 03:38
Last Modified: 27 Jan 2015 05:17

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