Contribution of oxidative damage to antimicrobial lethality.
A potential pathway linking hydroxyl radicals to antimicrobial lethality was examined by using mutational and chemical perturbations of Escherichia coli. Deficiencies of sodA or sodB had no effect on norfloxacin lethality; however, the absence of both genes together reduced lethal activity, consistent with rapid conversion of excessive superoxide to hydrogen peroxide contributing to quinolone lethality. Norfloxacin was more lethal with a mutant deficient in katG than with its isogenic parent, suggesting that detoxification of peroxide to water normally reduces quinolone lethality. An iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) reduced the lethal activity of norfloxacin, indicating that norfloxacin-stimulated accumulation of peroxide affects lethal activity via hydroxyl radicals generated through the Fenton reaction. Ampicillin and kanamycin, antibacterials unrelated to fluoroquinolones, displayed behavior similar to that of norfloxacin except that these two agents showed hyperlethality with an ahpC (alkyl hydroperoxide reductase) mutant rather than with a katG mutant. Collectively, these data are consistent with antimicrobial stress increasing the production of superoxide, which then undergoes dismutation to peroxide, from which a highly toxic hydroxyl radical is generated. Hydroxyl radicals then enhance antimicrobial lethality, as suggested by earlier work. Such findings indicate that oxidative stress networks may provide targets for antimicrobial potentiation.
Wang
Xiuhong
X
Public Health Research Institute, New Jersey Medical School-UMDNJ, Newark, NJ 07103, USA.
Zhao
Xilin
X
D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000502:physiology; D002374:Catalase / Q000502:physiology; D004926:Escherichia coli / Q000187:drug effects*; D029968:Escherichia coli Proteins / Q000502:physiology; D017665:Hydroxyl Radical; D008826:Microbial Sensitivity Tests; D009643:Norfloxacin / Q000494:pharmacology*; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000502:physiology; D013890:Thiourea / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D017665:Hydroxyl Radical; D015082:2,2'-Dipyridyl; C102664:hydroperoxidase II; D002374:Catalase; C051253:katG protein, E coli; C095500:SodA protein, Bacteria; C087504:SodB protein, Bacteria; D013482:Superoxide Dismutase; D013890:Thiourea; D009643:Norfloxacin