Document Detail


Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum.
MedLine Citation:
PMID:  23347134     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Resistance to antimalarials targeting the folate pathway is widespread. GTP-cyclohydrolase (gch1), the first enzyme in this pathway, exhibits extensive copy number variation (CN) in parasite isolates from areas with a history of longstanding antifolate use. Increased CN of gch1 is associated with a greater number of point mutations in enzymes targeted by the antifolates, pyrimethamine and sulphadoxine. While these observations suggest that increases in gch1 CN are an adaptation to drug pressure, changes in CN have not been experimentally demonstrated to directly alter drug susceptibility. To determine if changes in gch1 expression alone modify pyrimethamine sensitivity, we manipulated gch1 CN in several parasite lines to test the effect on drug sensitivity. We report that increases in gch1 CN alter pyrimethamine resistance in most parasites lines. However we find evidence of a detrimental effect of very high levels of gch1 overexpression in parasite lines with high endogenous levels of gch1 expression, revealing the importance of maintaining balance in the folate pathway and implicating changes in gch1 expression in preserving proper metabolic flux. This work expands our understanding of parasite adaptation to drug pressure and provides a possible mechanism for how specific mutations become fixed within parasite populations.
Authors:
Adina Heinberg; Edwin Siu; Chaya Stern; Elizabeth A Lawrence; Michael T Ferdig; Kirk W Deitsch; Laura A Kirkman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-04-24
Journal Detail:
Title:  Molecular microbiology     Volume:  88     ISSN:  1365-2958     ISO Abbreviation:  Mol. Microbiol.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-13     Completed Date:  2013-11-18     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8712028     Medline TA:  Mol Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  702-12     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons Ltd.
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MeSH Terms
Descriptor/Qualifier:
Adaptation, Biological*
Antimalarials / pharmacology*
Drug Resistance*
Folic Acid Antagonists / pharmacology*
Gene Dosage*
Genes, Protozoan
Plasmodium falciparum / drug effects*,  genetics*
Pyrimethamine / pharmacology
Grant Support
ID/Acronym/Agency:
AI 52390/AI/NIAID NIH HHS; AI 99327/AI/NIAID NIH HHS; AI76635/AI/NIAID NIH HHS; K08 AI076635/AI/NIAID NIH HHS; R01 AI052390/AI/NIAID NIH HHS; R01 AI099327/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antimalarials; 0/Folic Acid Antagonists; Z3614QOX8W/Pyrimethamine
Comments/Corrections

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