Molecular epidemiology of malaria in Cameroon. XXV. In vitro activity of fosmidomycin and its derivatives against fresh clinical isolates of Plasmodium falciparum and sequence analysis of 1-deoxy-D-xylulose 5-phosphate reductoisomerase.
The in vitro activities of fosmidomycin derivatives, chloroquine, and pyrimethamine were assessed by the radioisotopic assay in clinical isolates of Plasmodium falciparum. In a series of experiments with RPMI 1640 medium-10% fetal bovine serum, the geometric mean 50% inhibitory concentrations (IC(50)s) (n = 34) for fosmidomycin and FR900098 were 301 nM and 118 nM, respectively. In another series of experiments, the geometric mean IC(50)s (n = 33) for fosmidomycin and TH II46 were 413 nM and 249 nM, respectively. The IC(50)s were 2-3 times lower with RPMI-10% fetal bovine serum than the IC(50)s obtained with RPMI-10% human serum. FR900098 and TH II46 were 2.6 and 1.7 times more potent, respectively, than fosmidomycin. There was no correlation between chloroquine or pyrimethamine and fosmidomycin, which suggested the absence of in vitro cross-resistance. Sequence analysis showed five amino acid substitutions, but their possible relationship with the response to fosmidomycin is not clear. Fosmidomycin derivatives are promising candidates for further development.
Tahar
Rachida
R
Unité de Recherche 77 Paludologie Afro-Tropicale, Institut de Recherche pour le Développement, Organisation de Coordination pour la lutte contre les Endémies en Afrique Centrale, Yaoundé, Cameroon. rachidatahar@yahoo.fr
Basco
Leonardo K
LK
D000293:Adolescent; D019747:Aldose-Ketose Isomerases / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002163:Cameroon / Q000453:epidemiology; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology / Q000469:parasitology*; D017720:Molecular Epidemiology; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA
D016054:DNA, Protozoan; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases