A Common Mechanism of Cellular Death Induced by Bactericidal Antibiotics

Cell. 2007 Sep 7;130(5):797-810. doi: 10.1016/j.cell.2007.06.049.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 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

Substances

  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Escherichia coli Proteins
  • Ferrous Compounds
  • Free Radical Scavengers
  • Iron Chelating Agents
  • Membrane Proteins
  • tonB protein, E coli
  • NAD
  • Hydroxyl Radical
  • 2,2'-Dipyridyl
  • Kanamycin
  • Ampicillin
  • Hydrogen Peroxide
  • Rec A Recombinases
  • Carbon-Sulfur Lyases
  • cysteine desulfurase
  • Norfloxacin
  • Hydroxyurea