Killing by Bactericidal Antibiotics Does Not Depend on Reactive Oxygen Species

Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 021156, USA.
Science (Impact Factor: 33.61). 03/2013; 339(6124):1213-6. DOI: 10.1126/science.1232688
Source: PubMed


Bactericidal antibiotics kill by modulating their respective targets. This traditional view has been challenged by studies that propose an alternative, unified mechanism of killing, whereby toxic reactive oxygen species (ROS) are produced in the presence of antibiotics. We found no correlation between an individual cell's probability of survival in the presence of antibiotic and its level of ROS. An ROS quencher, thiourea, protected cells from antibiotics present at low concentrations, but the effect was observed under anaerobic conditions as well. There was essentially no difference in survival of bacteria treated with various antibiotics under aerobic or anaerobic conditions. This suggests that ROS do not play a role in killing of bacterial pathogens by antibiotics.

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    • "In mammalian cells, bactericidal antibiotics induce mitochondrial dysfunction by disrupting the electron transport chain, which triggers dose-and time-dependent overproduction of reactive oxygen species (ROS), thereby leading to oxidative stress damages (Kalghatgi et al. 2013). However, several reports demonstrated that ROS is not involved in bacterial cell death (Ezraty et al. 2013; Liu et al. 2013; Keren et al. 2013). Aberrant ROS production has always been associated with cellular oxidative damage and death. "
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    ABSTRACT: The aminoglycoside antibiotic hygromycin B (Hyg) inhibits prokaryotic, chloroplast and mitochondrial protein synthesis. Because of the toxic effect of Hyg on plant cells, the HPT gene, encoding hygromycin phosphotransferase, has become one of the most widely used selectable markers in plant transformation. Yet the mechanism behind Hyg-induced cell lethality in plants is not clearly understood. In this study, we aimed to decipher this mechanism. With Hyg treatment, rice calli exhibited cell death, and rice seedlings showed severe growth defects, leaf chlorosis and leaf shrinkage. Rice seedlings also exhibited severe lipid peroxidation and protein carbonylation, for oxidative stress damage at the cellular level. The production of reactive oxygen species such as O 2 (·-) , H2O2 and OH(·) was greatly induced in rice seedlings under Hyg stress, and pre-treatment with ascorbate increased resistance to Hyg-induced toxicity indicating the existence of oxidative stress. Overexpression of mitochondrial Alternative oxidase1a gene without HPT selection marker in rice enhanced tolerance to Hyg and attenuated the degradation of protein content, whereas the rice plastidial glutathione reductase 3 mutant showed increased sensitivity to Hyg. These results demonstrate that Hyg-induced cell lethality in rice is not only due to the inhibition of protein synthesis but also mediated by oxidative stress.
    Plant Molecular Biology 09/2015; DOI:10.1007/s11103-015-0380-4 · 4.26 Impact Factor
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    • "Recent studies, however, point to the existence of antibiotic killing mechanisms that are not dependent on OH • induction in bacteria (Brochmann et al., 2013; Keren et al., 2013; Liu & Imlay, 2013). For ciprofloxacin, this fits into a scheme containing two lethal pathways of quinolones: one is blocked by inhibitors of protein synthesis and by anaerobic conditions (the chloramphenicol-sensitive, ROS-dependent) and another is active even in the presence "

    • "Despite some controversy surrounding ROS and oxidative stress being central to bacterial killing by bactericidal antimicrobials (Keren et al. 2013; Kohanski et al. 2007; Liu and Imlay 2013), it would appear that ROS do contribute to antibiotic lethality (Dwyer et al. 2014), and thus, antioxidant or oxidative stress protective responses in bacteria should promote antimicrobial resistance. In this vein, Nguyen and co-workers have shown that the antibiotic tolerance of nutrient-limited biofilm cells of P. aeruginosa is attributed, in part, to antioxidant defenses that include catalases and their turnover of antibiotic-generated ROS (Khakimova et al. 2013; Nguyen et al. 2011). "
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    ABSTRACT: Pseudomonas aeruginosa is a notoriously antimicrobial-resistant organism that is increasingly refractory to antimicrobial chemotherapy. While the usual array of acquired resistance mechanisms contribute to resistance development in this organism a multitude of endogenous genes also play a role. These include a variety of multidrug efflux loci that contribute to both intrinsic and acquired antimicrobial resistance. Despite their roles in resistance, however, it is clear that these efflux systems function in more than just antimicrobial efflux. Indeed, recent data indicate that they are recruited in response to environmental stress and, therefore, function as components of the organism's stress responses. In fact, a number of endogenous resistance-promoting genes are linked to environmental stress, functioning as part of known stress responses or recruited in response to a variety of environmental stress stimuli. Stress responses are, thus, important determinants of antimicrobial resistance in P. aeruginosa. As such, they represent possible therapeutic targets in countering antimicrobial resistance in this organism.
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