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Origin of robustness in generating drug-resistant malaria parasites
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Metadata
Document Title
Origin of robustness in generating drug-resistant malaria parasites
Author
Kümpornsin K.,Modchang C.,Heinberg A.,Ekland E.H.,Jirawatcharadech P.,Chobson P.,Suwanakitti N.,Chaotheing S.,Wilairat P.,Deitsch K.W.,Kamchonwongpaisan S.,Fidock D.A.,Kirkman L.A.,Yuthavong Y.,Chookajorn T.
Name from Authors Collection
Scopus Author ID
37003044500
Affiliations
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand; Biophysics Group, Department of Physics, Mahidol University, Bangkok, Thailand; Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, United States; Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY, United States; National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani, Thailand; Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, United States; Division of Infectious Diseases, Department of Medicine, Weill Cornell Medical College, New York, NY, United States; Center of Excellence in Malaria, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
Type
Article
Source Title
Molecular Biology and Evolution
ISSN
07374038
Year
2014
Volume
31
Issue
7
Open Access
All Open Access, Bronze, Green
Publisher
Oxford University Press
DOI
10.1093/molbev/msu140
Abstract
Biological robustness allows mutations to accumulate while maintaining functional phenotypes. Despite its crucial role in evolutionary processes, the mechanistic details of how robustness originates remain elusive. Using an evolutionary trajectory analysis approach, we demonstrate how robustness evolved in malaria parasites under selective pressure from an antimalarial drug inhibiting the folate synthesis pathway. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. Nevertheless, the stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. Here, we report the epistatic interaction between dhfr mutations and amplification of the gene encoding the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and would thus be selected for by pyrimethamine treatment. Interestingly, the gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The compensation of compromised fitness by extra GCH1 is an example of how robustness can evolve in a system and thus expand the accessibility of evolutionary trajectories leading toward highly resistant alleles. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs. © The Author 2014.
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Funding Sponsor
National Institutes of Health; National Institute of Allergy and Infectious Diseases
License
CC BY-NC
Rights
Author
Publication Source
Scopus