RRC ID 3944
Author Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ.
Title A common mechanism of cellular death induced by bactericidal antibiotics.
Journal Cell
Abstract Antibiotic mode-of-action classification is based upon drug-target interaction and whether the resultant inhibition of cellular function is lethal to bacteria. Here we show that the three major classes of bactericidal antibiotics, regardless of drug-target interaction, stimulate the production of highly deleterious hydroxyl radicals in Gram-negative and Gram-positive bacteria, which ultimately contribute to cell death. We also show, in contrast, that bacteriostatic drugs do not produce hydroxyl radicals. We demonstrate that the mechanism of hydroxyl radical formation induced by bactericidal antibiotics is the end product of an oxidative damage cellular death pathway involving the tricarboxylic acid cycle, a transient depletion of NADH, destabilization of iron-sulfur clusters, and stimulation of the Fenton reaction. Our results suggest that all three major classes of bactericidal drugs can be potentiated by targeting bacterial systems that remediate hydroxyl radical damage, including proteins involved in triggering the DNA damage response, e.g., RecA.
Volume 130(5)
Pages 797-810
Published 2007-9-7
DOI 10.1016/j.cell.2007.06.049
PII S0092-8674(07)00899-9
PMID 17803904
MeSH 2,2'-Dipyridyl / pharmacology Ampicillin / pharmacology Anti-Bacterial Agents / classification Anti-Bacterial Agents / pharmacology* Carbon-Sulfur Lyases / genetics Carbon-Sulfur Lyases / metabolism Cell Death / drug effects Citric Acid Cycle / drug effects Citric Acid Cycle / genetics Colony Count, Microbial DNA Damage* DNA, Bacterial / drug effects* Escherichia coli / drug effects* Escherichia coli / genetics Escherichia coli / growth & development Escherichia coli / metabolism Escherichia coli Proteins / genetics Escherichia coli Proteins / metabolism Ferrous Compounds / metabolism Free Radical Scavengers / pharmacology Gene Expression Profiling Gene Expression Regulation, Bacterial / drug effects Hydrogen Peroxide / metabolism Hydroxyl Radical / metabolism* Hydroxyurea / pharmacology Iron Chelating Agents / pharmacology Kanamycin / pharmacology Membrane Proteins / genetics Membrane Proteins / metabolism Microbial Viability / drug effects* Mutation NAD / metabolism Norfloxacin / pharmacology Oxidative Stress / drug effects* Rec A Recombinases / genetics Rec A Recombinases / metabolism Staphylococcus aureus / drug effects* Staphylococcus aureus / genetics Staphylococcus aureus / growth & development Staphylococcus aureus / metabolism Time Factors
IF 36.216
Times Cited 980
Prokaryotes E. coli ME9062(BW25113)