Abstract:
:Chloroquine (CQ) was the best and most heavily used drug in the fight against malaria. However, the effectiveness of CQ has declined with the emergence and spread of CQ-resistant (CQR) Plasmodium falciparum parasites. The primary determinant of CQ resistance in P. falciparum is mutations in the parasite's 'chloroquine resistance transporter' (PfCRT). These mutations result in a marked reduction in the accumulation of CQ by the parasite; however the mechanism by which this is achieved was not understood. We have recently shown that the mutations confer upon PfCRT the ability to transport CQ away from its site of accumulation and action. Sensitive and resistance-conferring forms of the protein (PfCRT (CQS) and PfCRT (CQR) , respectively) were expressed at the surface of Xenopus laevis oocytes, and it was found that PfCRT (CQR) (but not PfCRT (CQS)) transports CQ. Here we discuss and expand upon our findings to address the question of whether PfCRT (CQR) behaves as a carrier or a channel, and how this distinction has significant implications for the treatment of CQR P. falciparum with CQ or CQ-like drugs. In particular we relate this to the example of Guinea-Bissau, where high doses of CQ are routinely used to treat CQR P. falciparum malaria.
journal_name
Virulencejournal_title
Virulenceauthors
Summers RL,Martin REdoi
10.4161/viru.1.4.12012subject
Has Abstractpub_date
2010-07-01 00:00:00pages
304-8issue
4eissn
2150-5594issn
2150-5608pii
12012journal_volume
1pub_type
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