title: 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.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Foti
authors.forename: Babho
authors.initials: B
authors.lastname: Devadoss
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Winkler
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: Graham C
authors.initials: GC
authors.lastname: Walker
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004256:DNA Polymerase I / Q000235:genetics / Q000378:metabolism; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism; D019951:DNA Polymerase beta / Q000235:genetics / Q000378:metabolism; D004269:DNA, Bacterial / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism*; D017665:Hydroxyl Radical / Q000378:metabolism; D007612:Kanamycin / Q000494:pharmacology; D050296:Microbial Viability; D008954:Models, Biological; D009643:Norfloxacin / Q000494:pharmacology; D010084:Oxidation-Reduction; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D012329:RNA, Bacterial / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D003848:Deoxyguanine Nucleotides; C094399:DinB protein, E coli; D029968:Escherichia coli Proteins; D006150:Guanine Nucleotides; D012329:RNA, Bacterial; C074431:polB protein, E coli; C078206:8-oxodeoxyguanosine triphosphate; D017665:Hydroxyl Radical; C024829:8-hydroxyguanine; D007612:Kanamycin; D006147:Guanine; D000667:Ampicillin; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D019951:DNA Polymerase beta; C120926:DNA polymerase V, E coli; D004259:DNA-Directed DNA Polymerase; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D011755:Pyrophosphatases; C052211:mutT protein, E coli; D009643:Norfloxacin