Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.
A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.
Jomaa
H
H
Institute of Biochemistry, Academic Hospital Centre, Justus-Liebig-University, Friedrichstrasse 24, D-35392 Giessen, Germany. hassan.jomaa@biochemie.med.uni-giessen.de
Wiesner
J
J
Sanderbrand
S
S
Altincicek
B
B
Weidemeyer
C
C
Hintz
M
M
Türbachova
I
I
Eberl
M
M
Zeidler
J
J
Lichtenthaler
H K
HK
Soldati
D
D
Beck
E
E
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017125:Genes, Protozoan; D045782:Hemiterpenes; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010428:Pentosephosphates / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013729:Terpenes / Q000494:pharmacology*
C109460:1-deoxylulose 5-phosphate; D000962:Antimalarials; D004791:Enzyme Inhibitors; D045782:Hemiterpenes; D009097:Multienzyme Complexes; D009943:Organophosphorus Compounds; D010428:Pentosephosphates; D011994:Recombinant Proteins; D013729:Terpenes; D005578:Fosfomycin; C004809:isopentenyl pyrophosphate; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases; D008798:Mevalonic Acid