Oxidation of the Guanine Nucleotide Pool Underlies Cell Death by Bactericidal Antibiotics
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- 20 April 2012
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 336 (6079), 315-319
- https://doi.org/10.1126/science.1219192
Abstract
A detailed understanding of the mechanisms that underlie antibiotic killing is important for the derivation of new classes of antibiotics and clinically useful adjuvants for current antimicrobial therapies. Our efforts to understand why DinB (DNA polymerase IV) overproduction is cytotoxic to Escherichia coli led to the unexpected insight that oxidation of guanine to 8-oxo-guanine in the nucleotide pool underlies much of the cell death caused by both DinB overproduction and bactericidal antibiotics. We propose a model in which the cytotoxicity of beta-lactams and quinolones predominantly results from lethal double-strand DNA breaks caused by incomplete repair of closely spaced 8-oxo-deoxyguanosine lesions, whereas the cytotoxicity of aminoglycosides might additionally result from mistranslation due to the incorporation of 8-oxo-guanine into newly synthesized RNAs.Keywords
This publication has 46 references indexed in Scilit:
- UmuD2 Inhibits a Non-covalent Step during DinB-mediated Template Slippage on Homopolymeric Nucleotide RunsPublished by Elsevier BV ,2010
- Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced MutagenesisMolecular Cell, 2010
- Hydroxyurea Induces Hydroxyl Radical-Mediated Cell Death in Escherichia coliMolecular Cell, 2009
- Critical amino acids in human DNA polymerases η and κ involved in erroneous incorporation of oxidized nucleotidesNucleic Acids Research, 2009
- Translesion DNA polymerases remodel the replisome and alter the speed of the replicative helicaseProceedings of the National Academy of Sciences of the United States of America, 2009
- Mistranslation of Membrane Proteins and Two-Component System Activation Trigger Antibiotic-Mediated Cell DeathCell, 2008
- Trace amounts of 8-oxo-dGTP in mitochondrial dNTP pools reduce DNA polymerase replication fidelityNucleic Acids Research, 2008
- Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coliMolecular Systems Biology, 2007
- Mechanisms of Formation, Genotoxicity, and Mutation of Guanine Oxidation ProductsChemical Research in Toxicology, 2006
- Construction of Escherichia coli K‐12 in‐frame, single‐gene knockout mutants: the Keio collectionMolecular Systems Biology, 2006