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Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum.
Gabryszewski, Stanislaw J; Modchang, Charin; Musset, Lise; Chookajorn, Thanat; Fidock, David A.
Afiliação
  • Gabryszewski SJ; Department of Microbiology and Immunology, Columbia University Medical Center, New York.
  • Modchang C; Department of Physics, Faculty of Science, Mahidol University, Bangkok, Thailand.
  • Musset L; Laboratoire de Parasitologie, WHO Collaborating Center for Surveillance of Anti-Malarial Drug Resistance, Institut Pasteur de la Guyane, Cayenne, French Guiana.
  • Chookajorn T; Genomics and Evolutionary Medicine Unit, Center of Excellence in Malaria, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
  • Fidock DA; Department of Microbiology and Immunology, Columbia University Medical Center, New York Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY df2260@columbia.edu.
Mol Biol Evol ; 33(6): 1554-70, 2016 06.
Article em En | MEDLINE | ID: mdl-26908582
ABSTRACT
The emergence of drug resistance continuously threatens global control of infectious diseases, including malaria caused by the protozoan parasite Plasmodium falciparum A critical parasite determinant is the P. falciparum chloroquine resistance transporter (PfCRT), the primary mediator of chloroquine (CQ) resistance (CQR), and a pleiotropic modulator of susceptibility to several first-line artemisinin-based combination therapy partner drugs. Aside from the validated CQR molecular marker K76T, P. falciparum parasites have acquired at least three additional pfcrt mutations, whose contributions to resistance and fitness have been heretofore unclear. Focusing on the quadruple-mutant Ecuadorian PfCRT haplotype Ecu1110 (K76T/A220S/N326D/I356L), we genetically modified the pfcrt locus of isogenic, asexual blood stage P. falciparum parasites using zinc-finger nucleases, producing all possible combinations of intermediate pfcrt alleles. Our analysis included the related quintuple-mutant PfCRT haplotype 7G8 (Ecu1110 + C72S) that is widespread throughout South America and the Western Pacific. Drug susceptibilities and in vitro growth profiles of our combinatorial pfcrt-modified parasites were used to simulate the mutational trajectories accessible to parasites as they evolved CQR. Our results uncover unique contributions to parasite drug resistance and growth for mutations beyond K76T and predict critical roles for the CQ metabolite monodesethyl-CQ and the related quinoline-type drug amodiaquine in driving mutant pfcrt evolution. Modeling outputs further highlight the influence of parasite proliferation rates alongside gains in drug resistance in dictating successful trajectories. Our findings suggest that P. falciparum parasites have navigated constrained pfcrt adaptive landscapes by means of probabilistically rare mutational bursts that led to the infrequent emergence of pfcrt alleles in the field.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Plasmodium falciparum / Resistência a Medicamentos / Proteínas de Protozoários Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Biol Evol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas de Membrana Transportadoras / Plasmodium falciparum / Resistência a Medicamentos / Proteínas de Protozoários Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Mol Biol Evol Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2016 Tipo de documento: Article