Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193) in field isolates and in W2 strain under pressure.
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.
Daher
Wassim
W
Inserm U547, Institut Pasteur, 1 rue du Pr Calmette, BP 245, 59019 Lille, France. wassim.daher@pasteur-lille.fr
Biot
Christophe
C
Fandeur
Thierry
T
Jouin
Helene
H
Pelinski
Lydie
L
Viscogliosi
Eric
E
Fraisse
Laurent
L
Pradines
Bruno
B
Brocard
Jacques
J
Khalife
Jamal
J
Dive
Daniel
D
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*
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