PMID:22517853
| Citation |
Foti, JJ, Devadoss, B, Winkler, JA, Collins, JJ and Walker, GC (2012) Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics. Science 336:315-9 |
|---|---|
| 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. |
| Links |
PubMed PMC3357493 Online version:10.1126/science.1219192 |
| Keywords |
Ampicillin/pharmacology; Anti-Bacterial Agents/pharmacology; DNA Breaks, Double-Stranded; DNA Glycosylases/genetics; DNA Glycosylases/metabolism; DNA Polymerase I/genetics; DNA Polymerase I/metabolism; DNA Polymerase II/genetics; DNA Polymerase II/metabolism; DNA Polymerase beta/genetics; DNA Polymerase beta/metabolism; DNA, Bacterial/metabolism; DNA-Directed DNA Polymerase/genetics; DNA-Directed DNA Polymerase/metabolism; Deoxyguanine Nucleotides/metabolism; Escherichia coli/drug effects; Escherichia coli/genetics; Escherichia coli/metabolism; Escherichia coli Proteins/genetics; Escherichia coli Proteins/metabolism; Guanine/analogs & derivatives; Guanine/metabolism; Guanine Nucleotides/metabolism; Hydroxyl Radical/metabolism; Kanamycin/pharmacology; Microbial Viability; Models, Biological; Norfloxacin/pharmacology; Oxidation-Reduction; Pyrophosphatases/genetics; Pyrophosphatases/metabolism; RNA, Bacterial/metabolism |
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