Report

Cell Death from Antibiotics Without the Involvement of Reactive Oxygen Species

Science  08 Mar 2013:
Vol. 339, Issue 6124, pp. 1210-1213
DOI: 10.1126/science.1232751

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Antibiotic Mechanisms Revisited

Several recent studies have suggested that bactericidal antibiotics kill cells by a common mechanism involving reactive oxygen species (ROS). Two groups tested this hypothesis using diverse experiments, with both finding that quinolone, lactam, and aminoglycoside antibiotics had similar efficacy for killing in the presence or absence of oxygen (or nitrate). Liu et al. (p. 1210) saw no increase in hydrogen peroxide production in antibiotic-exposed cells and found no association between antibiotic exposure and the expected symptoms of oxidative damage, such as the breakdown of iron-sulfur clusters in enzymes or of hydroxyl radical injuries to DNA. Similarly, Keren et al. (p. 1213) found no correlation between the production of ROS, inferred from hydroxyphenyl fluorescein dye measurements, and bacterial survival, nor was there any significant protective effect engendered by thiourea. The results do not support a common mode of action for bactericidal antibiotics mediated by ROS.

Abstract

Recent observations have suggested that classic antibiotics kill bacteria by stimulating the formation of reactive oxygen species (ROS). If true, this notion might guide new strategies to improve antibiotic efficacy. In this study, the model was directly tested. Contrary to the hypothesis, antibiotic treatment did not accelerate the formation of hydrogen peroxide in Escherichia coli and did not elevate intracellular free iron, an essential reactant for the production of lethal damage. Lethality persisted in the absence of oxygen, and DNA repair mutants were not hypersensitive, undermining the idea that toxicity arose from oxidative DNA lesions. We conclude that these antibiotic exposures did not produce ROS and that lethality more likely resulted from the direct inhibition of cell-wall assembly, protein synthesis, and DNA replication.

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