In vitro activity of ferroquine is independent of polymorphisms in transport protein genes implicated in quinoline resistance in Plasmodium falciparum.
The in vitro activity of ferroquine (FQ) (SR97193), a 4-aminoquinoline antimalarial compound that contains a ferrocenic nucleus, against 15 Plasmodium falciparum strains was assessed and compared with those of chloroquine (CQ), quinine (QN), monodesethylamodiaquine (MDAQ), and mefloquine (MQ). These 15 strains were genotyped for polymorphisms in quinoline resistance-associated genes such as Pfcrt, Pfmdr1, Pfmrp, and Pfnhe-1. FQ was highly active against CQ-resistant parasites or in parasites with reduced susceptibility to QN, MDAQ, or MQ. Encouragingly, we did not find a correlation between responses to FQ and those to other quinoline drugs. These results suggest that no cross-resistance exits between FQ and CQ or quinoline antimalarial drugs. Mutations in codons 74, 75, 76, 220, 271, 326, 356, and 371 of the Pfcrt gene; codons 86, 184, 1034, 1042, and 1246 of the Pfmdr1 gene; and codons 191 and 437 of the Pfmrp gene were not significantly associated with P. falciparum susceptibility to FQ. Neither the number of ms4760 DNNND or DDNHNDNHNN repeats in Pfnhe-1 nor the profile of ms4760 was significantly associated with the FQ in vitro response. These data suggest the FQ may not interact with transport proteins in quinoline-resistant parasites. The present results justify further clinical trials of FQ in multidrug resistance areas.
Henry
Maud
M
Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Parc le Pharo, 13998 Marseille Armées, France.
Briolant
Sébastien
S
Fontaine
Albin
A
Mosnier
Joel
J
Baret
Eric
E
Amalvict
Rémy
R
Fusaï
Thierry
T
Fraisse
Laurent
L
Rogier
Christophe
C
Pradines
Bruno
B
D000634:Aminoquinolines / Q000737:chemistry / Q000494:pharmacology*; D000655:Amodiaquine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002738:Chloroquine / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005296:Ferrous Compounds / Q000737:chemistry / Q000494:pharmacology*; D015767:Mefloquine / Q000737:chemistry / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics; D000075163:Metallocenes; D018895:Microsatellite Repeats / Q000235:genetics; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D015800:Protozoan Proteins / Q000235:genetics*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology
D000634:Aminoquinolines; D005296:Ferrous Compounds; D026901:Membrane Transport Proteins; D000075163:Metallocenes; D015800:Protozoan Proteins; D011804:Quinolines; D000655:Amodiaquine; C047386:desethylamodiaquine; D002738:Chloroquine; C479230:ferroquine; C037219:quinoline; D015767:Mefloquine