Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter |
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Authors: | Ines Petersen Stanislaw J Gabryszewski Geoffrey L Johnston Satish K Dhingra Andrea Ecker Rebecca E Lewis Mariana Justino de Almeida Judith Straimer Philipp P Henrich Eugene Palatulan David J Johnson Olivia Coburn‐Flynn Cecilia Sanchez Adele M Lehane Michael Lanzer David A Fidock |
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Institution: | 1. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA;2. Hygiene Institut, Abteilung Parasitologie, Universit?tsklinikum Heidelberg, Heidelberg, Germany;3. School of International and Public Affairs, Columbia University, New York, NY, USA;4. Department of Biological Sciences, Binghamton University, Binghamton, NY, USA;5. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA |
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Abstract: | The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within‐host competition with wild‐type drug‐sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild‐type pfcrt in co‐culture competition assays. These three alleles mediated cross‐resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first‐line artemisinin‐based combination therapy. These data reveal ongoing region‐specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine‐resistant malaria. |
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