Unbound MEDLINE

Oxidation of the guanine nucleotide pool underlies cell death by bactericidal antibiotics.

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.

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  • Authors

    Foti JJ, Devadoss B, Winkler JA, Collins JJ, Walker GC

    Source

    Science (New York, N.Y.) 336:6079 2012 Apr 20 pg 315-9

    MeSH

    Ampicillin
    Anti-Bacterial Agents
    DNA Breaks, Double-Stranded
    DNA Glycosylases
    DNA Polymerase I
    DNA Polymerase II
    DNA Polymerase beta
    DNA, Bacterial
    DNA-Directed DNA Polymerase
    Deoxyguanine Nucleotides
    Escherichia coli
    Escherichia coli Proteins
    Guanine
    Guanine Nucleotides
    Hydroxyl Radical
    Kanamycin
    Microbial Viability
    Models, Biological
    Norfloxacin
    Oxidation-Reduction
    Pyrophosphatases
    RNA, Bacterial

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22517853