title: Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure.
abstract: BACKGROUND
  Ferroquine (FQ), or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ) resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated.
  
  
  METHODS
  The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed.
  
  
  RESULTS
  The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT) or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments.
  
  
  CONCLUSIONS
  Field isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.
authors.affiliation: Inserm U547, Institut Pasteur, 1 rue du Pr Calmette, BP 245, 59019 Lille, France. wassim.daher@pasteur-lille.fr
authors.forename: Wassim
authors.initials: W
authors.lastname: Daher
authors.forename: Christophe
authors.initials: C
authors.lastname: Biot
authors.forename: Thierry
authors.initials: T
authors.lastname: Fandeur
authors.forename: Helene
authors.initials: H
authors.lastname: Jouin
authors.forename: Lydie
authors.initials: L
authors.lastname: Pelinski
authors.forename: Eric
authors.initials: E
authors.lastname: Viscogliosi
authors.forename: Laurent
authors.initials: L
authors.lastname: Fraisse
authors.forename: Bruno
authors.initials: B
authors.lastname: Pradines
authors.forename: Jacques
authors.initials: J
authors.lastname: Brocard
authors.forename: Jamal
authors.initials: J
authors.lastname: Khalife
authors.forename: Daniel
authors.initials: D
authors.lastname: Dive
mesh_terms: D000595:Amino Acid Sequence; D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001773:Blood Cells / Q000469:parasitology; D002478:Cells, Cultured; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics*; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry / Q000379:methods; D014644:Genetic Variation; D020128:Inhibitory Concentration 50; D026901:Membrane Transport Proteins / Q000235:genetics*; D000075163:Metallocenes; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D005296:Ferrous Compounds; D026901:Membrane Transport Proteins; D000075163:Metallocenes; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; D002738:Chloroquine; C479230:ferroquine