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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.

SUBMITTER: Foti JJ

PROVIDER: S-EPMC3357493 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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

Foti James J JJ Devadoss Babho B Winkler Jonathan A JA Collins James J JJ Walker Graham C GC

Science (New York, N.Y.) 20120401 6079

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 antibioti ...[more]

PMID: 22517853

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