Affiliation:
1. Kenya Medical Research Institute (KEMRI)/Wellcome Trust Collaborative Research Program, P.O. Box 230, 80108 Kilifi, Kenya
2. University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom
3. Institute of Hygiene, University of Heidelberg School of Medicine, Heidelberg, Germany
Abstract
ABSTRACT
Resistance to the amino alcohol quinine has been associated with polymorphisms in
pfnhe
, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance
in vitro
in isolates from Kenya. We analyzed
pfnhe
whole-gene polymorphisms, using capillary sequencing, and
pfcrt
at codon 76 (
pfcrt
-76) and
pfmdr1
at codon 86 (
pfmdr1
-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the
in vitro
activities of quinine and 2 amino alcohols, mefloquine and halofantrine.
In vitro
activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC
50
). The median IC
50
s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of
pfnhe
was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively;
P
< 0.05), while 3 repeats were associated with restoration of susceptibility. The decrease in susceptibility conferred by the 2 DNNND repeats was more pronounced in parasites harboring the
pfmdr1
-86 mutation. No association was found between susceptibility to quinine and the
pfcrt
-76 mutation or between susceptibility to mefloquine or halofantrine and the
pfnhe
gene and the
pfcrt
-76 and
pfmdr1
-86 mutations. Using previously published data on the
in vitro
activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with
pfnhe
polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437,
pfnhe
did not modulate their activities. Two DNNND repeats combined with the
pfmdr1
-86 mutation could be used as an indicator of reduced susceptibility to quinine.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
40 articles.
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