Editors' ChoiceAntibiotics

Reactive Species Contribute to Antibiotic-Mediated Killing

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Science Translational Medicine  28 May 2014:
Vol. 6, Issue 238, pp. 238ec92
DOI: 10.1126/scitranslmed.3009409

Antibiotics are designed to target bacteria selectively without damaging host cells. Reactive oxygen species (ROS), however, are more like berserkers. Although ROS are products of normal cellular metabolism, they contribute to oxidative damage against both microbial and host cells. ROS have been implicated in antibiotic-mediated lethality, but the mechanisms underlying this contribution remain unclear. The report by Dwyer et al. proposes a direct role of altered metabolism, respiration, and homoeostatis in ROS-mediated antibiotic lethality.

The authors estimated the production of ROS under antibiotic treatment by means of in vivo quantification of ROS on a diverse panel of fluorescent dyes with three different classes of antibiotics: β-lactams, aminoglycoside, and flouroquinolone. Treatment by different antibiotic classes induced different levels of ROS, indicating multiple routes of ROS generation. It was further reported that a quinolone-resistant strain did not produce detectable ROS on treatment with norfloxacin, thus indicating a crucial role of ROS in antibiotic lethality. These observations were also supported by using an assay to estimate intracellular ROS, a H2O2 sensor. Genetic reporter assay and microarray expression profiles under antibiotic treatment were compared with exogeneous H2O2; these tests indicated specific activation of oxidative stress regulon after antibiotic treatment. Elevated respiratory activity was one major source of ROS generation downstream of antibiotic exposure. Moreover, overexpression of MutS (a DNA mismatch repair enzyme) protected against antibiotic lethality, thus directly pointing to the role of DNA damage in cell death as a generic effect of antibiotics. The role of environmental factors in antibiotic lethality was also evaluated by use of an increased dosage of the H2O2-scavenging enzyme, KatG; addition of antioxidants such as glutathione and ascorbic acid; and an anaerobic environment. All limited antibiotic lethality to some extent. These observations highlight the role of molecular oxygen in the process but also indicate that ROS are contributors and not the sole reason for antibiotic-mediated killing.

The study reports that ROS production is not just an epiphenomenon of cell death but also directly contributes to antibiotic lethality. The study also emphasized the crucial role of experimental conditions (environmental factors) on ROS levels, as they constrain drug-induced ROS production. This study provides a comprehensive dimension to understanding antibiotic-mediated killing, which can be exploited to manipulate cell metabolism of pathogens in designing better therapeutics, specifically for the drug-resistant forms.

D. J. Dwyer et al., Antibiotics induce redox-related physiological alterations as part of their lethality. Proc. Natl. Acad. Sci. U.S.A., published online 6 May 2014 (10.1073/pnas.1401876111). [Abstract]

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