Isoprenoid biosynthesis as a drug target: bisphosphonate inhibition of Escherichia coli K12 growth and synergistic effects of fosmidomycin.
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.
Leon
Annette
A
Center for Biophysics and Computational Biology, University of Illinois at Urbana - Champaign, 607 South Mathews Avenue, Urbana, Illinois 61801, USA.
Liu
Lei
L
Yang
Yan
Y
Hudock
Michael P
MP
Hall
Patrick
P
Yin
Fenglin
F
Studer
Danielle
D
Puan
Kia-Joo
KJ
Morita
Craig T
CT
Oldfield
Eric
E
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D016000:Cluster Analysis; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004357:Drug Synergism; D048168:Escherichia coli K12 / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015870:Gene Expression; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis; D021281:Quantitative Structure-Activity Relationship; D013729:Terpenes / Q000037:antagonists & inhibitors*
D000900:Anti-Bacterial Agents; D004164:Diphosphonates; C517229:N-(methyl(4-phenylbutyl))-3-aminopropyl-1-hydroxy-1,1-bisphosphonate; D013729:Terpenes; D005578:Fosfomycin; C024640:fosmidomycin; D051228:Geranyltranstransferase