สืบค้นงานวิจัย
Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum
Gabryszewski S.J. - ไม่ระบุหน่วยงาน
ชื่อเรื่อง (EN): Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum
ผู้แต่ง / หัวหน้าโครงการ (EN): Gabryszewski S.J.
บทคัดย่อ (EN): 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. © 2016 The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
บทคัดย่อ: ไม่พบข้อมูลจากหน่วยงานต้นทาง
ภาษา (EN): en
เอกสารแนบ (EN): https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964581380&doi=10.1093%2fmolbev%2fmsw037&partnerID=40&md5=21842be8a6a12749fbeb74178326c6ab
เผยแพร่โดย (EN): มหาวิทยาลัยมหิดล
คำสำคัญ (EN): unclassified drug
เจ้าของลิขสิทธิ์ (EN): มหาวิทยาลัยมหิดล
หากไม่พบเอกสารฉบับเต็ม (Full Text) โปรดติดต่อหน่วยงานเจ้าของข้อมูล

การอ้างอิง

Gabryszewski S.J.. "Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum". ไม่ระบุหน่วยงาน. ม.ป.ป.

Gabryszewski S.J.. "Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum". ไม่ระบุหน่วยงาน. ม.ป.ป.. Print.



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Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum
Gabryszewski S.J.
มหาวิทยาลัยมหิดล
ไม่ระบุวันที่เผยแพร่
Prevalence of Plasmodium falciparum molecular markers of antimalarial drug resistance in a residual malaria focus area in Sabah, Malaysia Evolution of Fseg/Cseg dimorphism in region III of the Plasmodium falciparum eba-175 gene Neutralizing antibodies against Plasmodium falciparum associated with successful cure after drug therapy Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance Genetic diversity of the Plasmodium vivax multidrug resistance 1 gene in Thai parasite populations Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China-Myanmar border area Artemisinin-resistant Plasmodium falciparum malaria Genetic diversity of plasmodium falciparum populations in malaria declining areas of Sabah, East Malaysia Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance Single nucleotide polymorphisms in Plasmodium falciparum V type H+ pyrophosphatase gene (pfvp2) and their associations with pfcrt and pfmdr1 polymorphisms
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