Journal article
Isoprenoid biosynthesis as a drug target : Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin
Journal of medicinal chemistry, Vol.49(25), pp.7331-7341
2006
DOI: 10.1021/jm060492b
PMID: 17149863
Abstract
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.
Details
- Title: Subtitle
- Isoprenoid biosynthesis as a drug target : Bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin
- Creators
- Annette LEON - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesLEI LIU - W. M. Keck Center for Comparative and Functional Genomics, University of Illinois at Urbana-Champaign, 1201 West Gregory Drive, Urbana, Illinois 61801, United StatesYAN YANG - Department of Statistics, University of Illinois at Urbana-Champaign, 725 South Wright Street, Champaign, Illinois 61820, United StatesMichael P HUDOCK - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesPatrick HALL - Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United StatesFENGLIN YIN - Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, United StatesDanielle STUDER - School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, 505 South Goodwin Ave, Urbana, Illinois 61801, United StatesKia-Joo PUAN - Division of Rheumatology, Department of Internal Medicine and the Interdisciplinary Group in Immunology, University of Iowa College of Medicine, EMRB 400, Iowa City, Iowa 52242, United StatesCraig T MORITA - Division of Rheumatology, Department of Internal Medicine and the Interdisciplinary Group in Immunology, University of Iowa College of Medicine, EMRB 400, Iowa City, Iowa 52242, United StatesEric OLDFIELD - Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, United States
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.49(25), pp.7331-7341
- DOI
- 10.1021/jm060492b
- PMID
- 17149863
- NLM abbreviation
- J Med Chem
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Publisher
- American Chemical Society
- Language
- English
- Date published
- 2006
- Academic Unit
- Immunology; Internal Medicine
- Record Identifier
- 9984094657802771
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