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

Publisher Full Text

Authors

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

Institution

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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