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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Assessing the cost-benefit effect of a plasmodium falciparum drug resistance mutation on parasite growth in vitro
Antimicrobial Agents and Chemotherapy, Volume 57, No. 2, Year 2013
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Description
Plasmodium falciparum mutations associated with antimalarial resistance may be beneficial for parasites under drug pressure, although they may also cause a fitness cost. We herein present an in vitro model showing how this combined effect on parasite growth varies with the drug concentration and suggest a calculated drug-specific cost-benefit index, indicating the possible advantage for mutated parasites. We specifically studied the D-to-Y change at position 1246 encoded by the pfmdr1 gene (pfmdr1 D1246Y) in relation to amodiaquine resistance. Susceptibilities to amodiaquine, desethylamodiaquine, and chloroquine, as well as relative fitness, were determined for two modified isogenic P. falciparum clones differing only in the pfmdr1 1246 position. Data were used to create a new comparative graph of relative growth in relation to the drug concentration and to calculate the ratio between the benefit of resistance and the fitness cost. Results were related to an in vivo allele selection analysis after amodiaquine or artesunate-amodiaquine treatment. pfmdr1 1246Y was associated with decreased susceptibility to amodiaquine and desethylamodiaquine but at a growth fitness cost of 11%. Mutated parasites grew less in low drug concentrations due to a predominating fitness cost, but beyond a breakpoint concentration they grew more due to a predominating benefit of increased resistance. The cost-benefit indexes indicated that pfmdr1 1246Y was most advantageous for amodiaquine-exposed parasites. In vivo, a first drug selection of mutant parasites followed by a fitness selection of wild-type parasites supported the in vitro data. This cost-benefit model may predict the risk for selection of drug resistance mutations in different malaria transmission settings. Copyright © 2013, American Society for Microbiology. All Rights Reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3553735/bin/supp_57_2_887__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3553735/bin/AAC.00950-12_zac999101575so1.pdf
Authors & Co-Authors
Fröberg, Gabrielle
Sweden, Stockholm
Karolinska Institutet
Ferreira, Pedro Eduardo
Sweden, Stockholm
Karolinska Institutet
Portugal, Faro
Universidade do Algarve
Mårtensson, Andreas A.
Sweden, Stockholm
Karolinska Institutet
Ali, Abdullah Suleiman
Tanzania, Mkokotoni, Zanzibar
Zanzibar Malaria Control Programme Zmcp
Bjǒrkman, Anders B.
Portugal, Faro
Universidade do Algarve
Gilb, José Pedro
United States, Binghamton
Binghamton University State University of new York
Sweden, Stockholm
Karolinska Institutet
Statistics
Citations: 25
Authors: 6
Affiliations: 4
Identifiers
Doi:
10.1128/AAC.00950-12
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Cancer
Genetics And Genomics
Infectious Diseases