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A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine

Satish Kumar Dhingra; Devasha Redhi; Jill M. Combrinck; Tomas Yeo; John Okombo; Philipp P. Henrich; Annie N. Cowell; Purva Gupta; Matthew L. Stegman; Jonathan M. Hoke; Roland A. Cooper; Elizabeth Winzeler; Sachel Shu Li Mok; Timothy J. Egan; David Armand Fidock

Title:
A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine
Author(s):
Dhingra, Satish Kumar
Redhi, Devasha
Combrinck, Jill M.
Yeo, Tomas
Okombo, John
Henrich, Philipp P.
Cowell, Annie N.
Gupta, Purva
Stegman, Matthew L.
Hoke, Jonathan M.
Cooper, Roland A.
Winzeler, Elizabeth
Mok, Sachel Shu Li
Egan, Timothy J.
Fidock, David Armand
Date:
Type:
Articles
Department(s):
Microbiology and Immunology
Medicine
Volume:
8
Persistent URL:
Book/Journal Title:
mBio
Geographic Area:
Asia
Abstract:
Current efforts to reduce the global burden of malaria are threatened by the rapid spread throughout Asia of Plasmodium falciparum resistance to artemisinin-based combination therapies, which includes increasing rates of clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition of the C101F mutation to the chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common to Asia can confer PPQ resistance to cultured parasites. Resistance was demonstrated as significantly higher PPQ concentrations causing 90% inhibition of parasite growth (IC90) or 50% parasite killing (50% lethal dose [LD50]). This mutation also reversed Dd2-mediated CQ resistance, sensitized parasites to amodiaquine, quinine, and artemisinin, and conferred amantadine and blasticidin resistance. Using heme fractionation assays, we demonstrate that PPQ causes a buildup of reactive free heme and inhibits the formation of chemically inert hemozoin crystals. Our data evoke inhibition of heme detoxification in the parasite’s acidic digestive vacuole as the primary mode of both the bis-aminoquinoline PPQ and the related 4-aminoquinoline CQ. Both drugs also inhibit hemoglobin proteolysis at elevated concentrations, suggesting an additional mode of action. Isogenic lines differing in their pfmdr1 copy number showed equivalent PPQ susceptibilities. We propose that mutations in PfCRT could contribute to a multifactorial basis of PPQ resistance in field isolates.
Subject(s):
Plasmodium falciparum
Microbiology
Antimalarials
Biology
Publisher DOI:
https://doi.org/10.1128/mBio.00303-17
Item views
17
Metadata:
text | xml
Suggested Citation:
Satish Kumar Dhingra, Devasha Redhi, Jill M. Combrinck, Tomas Yeo, John Okombo, Philipp P. Henrich, Annie N. Cowell, Purva Gupta, Matthew L. Stegman, Jonathan M. Hoke, Roland A. Cooper, Elizabeth Winzeler, Sachel Shu Li Mok, Timothy J. Egan, David Armand Fidock, , A Variant PfCRT Isoform Can Contribute to Plasmodium falciparum Resistance to the First-Line Partner Drug Piperaquine, Columbia University Academic Commons, .

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