Evidence for the early emergence of piperaquine-resistant Plasmodium falciparum malaria and modeling strategies to mitigate resistance.

Autor: Small-Saunders JL; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Hagenah LM; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, United States of America., Wicht KJ; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, United States of America., Dhingra SK; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, United States of America., Deni I; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, United States of America., Kim J; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York United States of America., Vendome J; Schrödinger, Inc., New York, New York, United States of America., Gil-Iturbe E; Department of Psychiatry, Columbia University Irving Medical Center, New York, New York, United States of America., Roepe PD; Department of Chemistry, Georgetown University, Washington, DC, United States of America.; Department of Biochemistry and Cellular and Molecular Biology, Georgetown University, Washington, DC, United States of America., Mehta M; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States of America., Mancia F; Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, New York United States of America., Quick M; Department of Psychiatry, Columbia University Irving Medical Center, New York, New York, United States of America.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York, United States of America.; Center for Molecular Recognition, Columbia University Irving Medical Center, New York, New York, United States of America., Eppstein MJ; Vermont Complex Systems Center, University of Vermont, Burlington, Vermont, United States of America.; Department of Computer Science, University of Vermont, Burlington, Vermont, United States of America.; Translational Global Infectious Diseases Research Center, University of Vermont, Burlington, Vermont, United States of America., Fidock DA; Center for Malaria Therapeutics and Antimicrobial Resistance, Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, United States of America.; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, New York, United States of America.
Jazyk: angličtina
Zdroj: PLoS pathogens [PLoS Pathog] 2022 Feb 07; Vol. 18 (2), pp. e1010278. Date of Electronic Publication: 2022 Feb 07 (Print Publication: 2022).
DOI: 10.1371/journal.ppat.1010278
Abstrakt: Multidrug-resistant Plasmodium falciparum parasites have emerged in Cambodia and neighboring countries in Southeast Asia, compromising the efficacy of first-line antimalarial combinations. Dihydroartemisinin + piperaquine (PPQ) treatment failure rates have risen to as high as 50% in some areas in this region. For PPQ, resistance is driven primarily by a series of mutant alleles of the P. falciparum chloroquine resistance transporter (PfCRT). PPQ resistance was reported in China three decades earlier, but the molecular driver remained unknown. Herein, we identify a PPQ-resistant pfcrt allele (China C) from Yunnan Province, China, whose genotypic lineage is distinct from the PPQ-resistant pfcrt alleles currently observed in Cambodia. Combining gene editing and competitive growth assays, we report that PfCRT China C confers moderate PPQ resistance while re-sensitizing parasites to chloroquine (CQ) and incurring a fitness cost that manifests as a reduced rate of parasite growth. PPQ transport assays using purified PfCRT isoforms, combined with molecular dynamics simulations, highlight differences in drug transport kinetics and in this transporter's central cavity conformation between China C and the current Southeast Asian PPQ-resistant isoforms. We also report a novel computational model that incorporates empirically determined fitness landscapes at varying drug concentrations, combined with antimalarial susceptibility profiles, mutation rates, and drug pharmacokinetics. Our simulations with PPQ-resistant or -sensitive parasite lines predict that a three-day regimen of PPQ combined with CQ can effectively clear infections and prevent the evolution of PfCRT variants. This work suggests that including CQ in combination therapies could be effective in suppressing the evolution of PfCRT-mediated multidrug resistance in regions where PPQ has lost efficacy.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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