期刊
MOLECULAR CELL
卷 15, 期 6, 页码 867-877出版社
CELL PRESS
DOI: 10.1016/j.molcel.2004.09.012
关键词
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资金
- NIAID NIH HHS [R01 AI50234, R01 AI050234-05, R01 AI050234, R37 AI050234] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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.
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