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<jats:title>ABSTRACT</jats:title> <jats:p>Resistance to the amino alcohol quinine has been associated with polymorphisms in <jats:italic>pfnhe</jats:italic>, a sodium hydrogen exchanger. We investigated the role of this gene in quinine resistance <jats:italic>in vitro</jats:italic> in isolates from Kenya. We analyzed <jats:italic>pfnhe</jats:italic> whole-gene polymorphisms, using capillary sequencing, and <jats:italic>pfcrt</jats:italic> at codon 76 (<jats:italic>pfcrt</jats:italic>-76) and <jats:italic>pfmdr1</jats:italic> at codon 86 (<jats:italic>pfmdr1</jats:italic>-86), using PCR-enzyme restriction methodology, in 29 isolates from Kilifi, Kenya, for association with the <jats:italic>in vitro</jats:italic> activities of quinine and 2 amino alcohols, mefloquine and halofantrine. <jats:italic>In vitro</jats:italic> activity was assessed as the drug concentration that inhibits 50% of parasite growth (IC<jats:sub>50</jats:sub>). The median IC<jats:sub>50</jats:sub>s of quinine, halofantrine, and mefloquine were 92, 22, and 18 nM, respectively. The presence of 2 DNNND repeats in microsatellite ms4760 of <jats:italic>pfnhe</jats:italic> was associated with reduced susceptibility to quinine (60 versus 227 nM for 1 and 2 repeats, respectively; <jats:italic>P</jats:italic> &lt; 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 <jats:italic>pfmdr1</jats:italic>-86 mutation. No association was found between susceptibility to quinine and the <jats:italic>pfcrt</jats:italic>-76 mutation or between susceptibility to mefloquine or halofantrine and the <jats:italic>pfnhe</jats:italic> gene and the <jats:italic>pfcrt</jats:italic>-76 and <jats:italic>pfmdr1</jats:italic>-86 mutations. Using previously published data on the <jats:italic>in vitro</jats:italic> activities of chloroquine, lumefantrine, piperaquine, and dihydroartemisinin, we investigated the association of their activities with <jats:italic>pfnhe</jats:italic> polymorphism. With the exception of a modulation of the activity of lumefantrine by a mutation at position 1437, <jats:italic>pfnhe</jats:italic> did not modulate their activities. Two DNNND repeats combined with the <jats:italic>pfmdr1</jats:italic>-86 mutation could be used as an indicator of reduced susceptibility to quinine.</jats:p>

Original publication

DOI

10.1128/aac.00325-10

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

08/2010

Volume

54

Pages

3302 - 3307