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Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents

Johnson, David, Fidock, D. A., Mungthin, M., Lakshmanan, V., Sidhu, A. B. S., Bray, Patrick and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2004) 'Evidence for a central role for PfCRT in conferring Plasmodium falciparum resistance to diverse antimalarial agents'. Molecular Cell, Vol 15, Issue 6, pp. 867-877.

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Abstract

Chloroquine resistance in Plasmodium falciparum is primarily conferred by mutations in pfcrt. Parasites resistant to chloroquine can display hypersensitivity to other antimalarials; however, the patterns of cross-resistance are complex, and the genetic basis has remained elusive. We show that stepwise selection for resistance to amantadine or halofantrine produced previously unknown pfcrt mutations (including S163R), which were associated with a loss of verapamil-reversible chloroquine resistance. This was accompanied by restoration of efficient chloroquine binding to hematin in these selected lines. This S163R mutation provides insight into a mechanism by which PfCRT could gate the transport of protonated chloroquine through the digestive vacuole membrane. Evidence for the presence of this mutation in a Southeast Asian isolate supports the argument for a broad role for PfCRT in determining levels of susceptibility to structurally diverse antimalarials.

Item Type: Article
Uncontrolled Keywords: transmembrane protein pfcrt human malaria parasites digestive vacuolar ph chloroquine-resistance drug-resistance in-vitro halofantrine resistance cross-resistance pfmdr1 gene mefloquine resistance
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified.
QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department: Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI): https://doi.org/10.1016/j.molcel.2004.09.012
Depositing User: Ms Julia Martin
Date Deposited: 24 Feb 2012 12:28
Last Modified: 06 Feb 2018 13:03
URI: http://archive.lstmed.ac.uk/id/eprint/2205

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