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

Annette Leon, Lei Liu, Yan Yang, Michael P. Hudock, Patrick Hall, Fenglin Yin, Danielle Studer, Kia Joo Puan, Craig T. Morita, Eric Oldfield

Research output: Contribution to journalArticle

Abstract

We screened a library of 117 bisphosphonates for antibacterial activity against Escherichia coli. The most potent growth inhibitors where the 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.

Original languageEnglish (US)
Pages (from-to)7331-7341
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number25
DOIs
StatePublished - Dec 14 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Isoprenoid biosynthesis as a drug target: Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin'. Together they form a unique fingerprint.

  • Cite this