Journal
SCIENCE
Volume 336, Issue 6079, Pages 315-319Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1219192
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Funding
- NIH [R01 CA021615, F32 GM079885, DP1 OD003644, P30 ES002019]
- Howard Hughes Medical Institute
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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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