Isoprenoid biosynthesis as a target for antibacterial and antiparasitic drugs: phosphonohydroxamic acids as inhibitors of deoxyxylulose phosphate reducto-isomerase

Biochem J. 2005 Feb 15;386(Pt 1):127-35. doi: 10.1042/BJ20041378.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Antimalarials / chemical synthesis
  • Antimalarials / pharmacology*
  • Butyrates / chemical synthesis
  • Butyrates / pharmacology
  • Drug Design
  • Drug Resistance, Multiple, Bacterial
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / pharmacology
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / pharmacology*
  • Microbial Sensitivity Tests
  • Multienzyme Complexes / antagonists & inhibitors*
  • NADP / metabolism
  • Organophosphonates / chemical synthesis
  • Organophosphonates / pharmacology*
  • Oxidoreductases / antagonists & inhibitors*
  • Terpenes / metabolism*

Substances

  • 4-((hydroxy(methyl)amino)-4-oxobutyl)phosphonic acid
  • 4-(hydroxyamino)-4-oxobutylphosphonic acid
  • Anti-Bacterial Agents
  • Antimalarials
  • Butyrates
  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Hydroxamic Acids
  • Multienzyme Complexes
  • Organophosphonates
  • Terpenes
  • Fosfomycin
  • NADP
  • fosmidomycin
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases