Isoprenoid biosynthesis as a drug target: bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin

J Med Chem. 2006 Dec 14;49(25):7331-41. doi: 10.1021/jm060492b.


We screened a library of 117 bisphosphonates for antibacterial activity against Escherichia coli. The most potent growth inhibitors where N-[methyl(4-phenylalkyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonates, known potent bone resorption inhibitors, and there was a generally good correlation between cell growth inhibition and E. coli farnesyl diphosphate synthase (FPPS) inhibition. However, some potent FPPS inhibitors had no activity in cell growth inhibition, and based on the result of Catalyst pharmacophore modeling, this could be attributed to the requirement of a large hydrophobic feature for cellular activity (due most likely to transport). The activity of the most potent compound, N-[methyl(4-phenylbutyl)]-3-aminopropyl-1-hydroxy-1,1-bisphosphonate (13), was strongly potentiated by the drug fosmidomycin. The transcription profiles for 13 or fosmidomycin alone were different from those found with carbenicillin or ciprofloxacin alone, but there were many similarities between the combination (13-fosmidomycin) and carbenicillin or ciprofloxacin, reflecting the more potent bactericidal activity of the drug combination on bacterial growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Cluster Analysis
  • Diphosphonates / chemistry
  • Diphosphonates / pharmacology*
  • Drug Synergism
  • Escherichia coli K12 / drug effects*
  • Escherichia coli K12 / growth & development
  • Escherichia coli K12 / metabolism
  • Fosfomycin / analogs & derivatives*
  • Fosfomycin / pharmacology
  • Gene Expression
  • Geranyltranstransferase / antagonists & inhibitors
  • Geranyltranstransferase / chemistry
  • Models, Molecular
  • Oligonucleotide Array Sequence Analysis
  • Quantitative Structure-Activity Relationship
  • Terpenes / antagonists & inhibitors*


  • Anti-Bacterial Agents
  • Diphosphonates
  • N-(methyl(4-phenylbutyl))-3-aminopropyl-1-hydroxy-1,1-bisphosphonate
  • Terpenes
  • Fosfomycin
  • fosmidomycin
  • Geranyltranstransferase