A common mechanism of cellular death induced by bactericidal antibiotics.
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.
Kohanski
Michael A
MA
Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA 02215, USA.
Dwyer
Daniel J
DJ
Hayete
Boris
B
Lawrence
Carolyn A
CA
Collins
James J
JJ
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000145:classification / Q000494:pharmacology*; D013437:Carbon-Sulfur Lyases / Q000235:genetics / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects / Q000235:genetics; D015169:Colony Count, Microbial; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D005296:Ferrous Compounds / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D006918:Hydroxyurea / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D007612:Kanamycin / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D050296:Microbial Viability / Q000187:drug effects*; D009154:Mutation; D009243:NAD / Q000378:metabolism; D009643:Norfloxacin / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011938:Rec A Recombinases / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D013997:Time Factors