Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase.
Isoprenoid biosynthesis via the methylerythritol phosphate pathway is a target against pathogenic bacteria and the malaria parasite Plasmodium falciparum. 4-(Hydroxyamino)-4-oxobutylphosphonic acid and 4-[hydroxy(methyl)amino]-4-oxobutyl phosphonic acid, two novel inhibitors of DXR (1-deoxy-D-xylulose 5-phosphate reducto-isomerase), the second enzyme of the pathway, have been synthesized and compared with fosmidomycin, the best known inhibitor of this enzyme. The latter phosphonohydroxamic acid showed a high inhibitory activity towards DXR, much like fosmidomycin, as well as significant antibacterial activity against Escherichia coli in tests on Petri dishes.
Université Louis Pasteur/CNRS-UMR 7123, Institut Le Bel, 4 rue Blaise Pascal, 67070 Strasbourg Cedex, France.
Lionel
L
Kuntz
Denis
D
Tritsch
Catherine
C
Grosdemange-Billiard
Andréa
A
Hemmerlin
Audrey
A
Willem
Thomas J
TJ
Bach
Michel
M
Rohmer
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D002087:Butyrates / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D024901:Drug Resistance, Multiple, Bacterial; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009249:NADP / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013729:Terpenes / Q000378:metabolism*
C502445:4-((hydroxy(methyl)amino)-4-oxobutyl)phosphonic acid; C502446:4-(hydroxyamino)-4-oxobutylphosphonic acid; D000900:Anti-Bacterial Agents; D000962:Antimalarials; D002087:Butyrates; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D006877:Hydroxamic Acids; D009097:Multienzyme Complexes; D063065:Organophosphonates; D013729:Terpenes; D005578:Fosfomycin; D009249:NADP; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases