Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum

PLoS One. 2018 Jan 17;13(1):e0191084. doi: 10.1371/journal.pone.0191084. eCollection 2018.

Abstract

Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Antimalarials / administration & dosage
  • Antimalarials / pharmacology*
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacology*
  • DNA, Protozoan / genetics
  • DNA, Protozoan / isolation & purification
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Genotype
  • Inhibitory Concentration 50
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / physiology
  • Polymerase Chain Reaction

Substances

  • Antimalarials
  • Artemisinins
  • DNA, Protozoan
  • artemisinin

Grants and funding

This study was supported by a gift from ARAM-Onlus. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.