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<jats:title>ABSTRACT</jats:title><jats:p>The<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content>genome is rich in regions of low amino acid complexity which evolve with few constraints on size. To explore the extent of diversity in these loci, we sequenced repeat regions in<jats:italic>pfmdr1</jats:italic>,<jats:italic>pfmdr5</jats:italic>,<jats:italic>pfmdr6</jats:italic>,<jats:italic>pfmrp2</jats:italic>, and the antigenic locus<jats:italic>pfmsp8</jats:italic>in laboratory and cultured-adapted clinical isolates. We further assessed associations between the repeats and parasite<jats:italic>in vitro</jats:italic>responses to 7 antimalarials to determine possible adaptive roles of these repeats in drug tolerance. Our results show extensive repeat variations in the reference and clinical isolates in all loci. We also observed a modest increase in dihydroartemisinin activity in parasites harboring the<jats:italic>pfmdr1</jats:italic>sequence profile 7-2-10 (reflecting the number of asparagine repeats, number of aspartate repeats, and number of asparagine repeats in the final series of the gene product) (<jats:italic>P</jats:italic>= 0.0321) and reduced sensitivity to chloroquine, mefloquine, quinine, and dihydroartemisinin in those with the 7-2-11 profile (<jats:italic>P</jats:italic>= 0.0051, 0.0068, 0.0011, and 0.0052, respectively). Interestingly, we noted an inverse association between two drugs whereby isolates with 6 asparagine repeats encoded by<jats:italic>pfmdr6</jats:italic>were significantly more susceptible to piperaquine than those with 8 (<jats:italic>P</jats:italic>= 0.0057). Against lumefantrine, those with 8 repeats were, however, more sensitive (<jats:italic>P</jats:italic>= 0.0144). In<jats:italic>pfmrp2</jats:italic>, the 7-<jats:underline>D</jats:underline>NNNTS/<jats:underline>N</jats:underline>NNNTS (number of DNNNTS or NNNNTS motifs; underlining indicates dimorphism) repeat group was significantly associated with a higher lumefantrine 50% inhibitory concentration (IC<jats:sub>50</jats:sub>) (<jats:italic>P</jats:italic>= 0.008) than in those without. No associations were observed with<jats:italic>pfmsp8</jats:italic>. These results hint at the probable utility of some repeat conformations as markers of<jats:italic>in vitro</jats:italic>antimalarial response; hence, biochemical functional studies to ascertain their role in<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content>are required.</jats:p>

Original publication

DOI

10.1128/aac.01465-13

Type

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

12/2013

Volume

57

Pages

6196 - 6204