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<jats:title>ABSTRACT</jats:title><jats:p>The 4-aminoquinoline bisquinoline piperaquine is an important partner drug in one of the presently recommended artemisinin combination therapies. Recent clinical trials have confirmed its high efficacy in combination with dihydroartemisinin. Resistance to piperaquine alone has, however, been documented. Amplification in copy number of the<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>multidrug resistance locus on chromosome 5, containing the<jats:italic>pfmdr1</jats:italic>gene, has been shown to confer resistance to structurally unrelated antimalarials. Through the determination of the 50% inhibitory concentrations (IC<jats:sub>50</jats:sub>s) and IC<jats:sub>90</jats:sub>s for piperaquine and chloroquine in a set of 46 adapted<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>cultures originating from the Thai-Burmese border, we have characterized the regions around the<jats:italic>pfmdr1</jats:italic>gene and identified a significant association between the presence of<jats:italic>pfmdr1</jats:italic>duplications and enhanced sensitivity to piperaquine (<jats:italic>P</jats:italic>= 0.005 for IC<jats:sub>50</jats:sub>and<jats:italic>P</jats:italic>= 0.002 for IC<jats:sub>90</jats:sub>) and chloroquine, reaching statistical significance at IC<jats:sub>90</jats:sub>s (<jats:italic>P</jats:italic>= 0.026). These results substantiate the potential importance of<jats:italic>pfmdr1</jats:italic>copy number amplifications in the efficacy of the combination therapy piperaquine-dihydroartemisinin. It supports the rational use of 4-aminoquinolines and artemisinin-based compounds, as they independently select for mutually incompatible combinations of mutations.</jats:p>

Original publication

DOI

10.1128/aac.06350-11

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

07/2012

Volume

56

Pages

3615 - 3619