89
views
0
recommends
+1 Recommend
0 collections
    5
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Gyrase inhibitors induce an oxidative damage cellular death pathway in Escherichia coli

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Modulation of bacterial chromosomal supercoiling is a function of DNA gyrase-catalyzed strand breakage and rejoining. This reaction is exploited by both antibiotic and proteic gyrase inhibitors, which trap the gyrase molecule at the DNA cleavage stage. Owing to this interaction, double-stranded DNA breaks are introduced and replication machinery is arrested at blocked replication forks. This immediately results in bacteriostasis and ultimately induces cell death. Here we demonstrate, through a series of phenotypic and gene expression analyses, that superoxide and hydroxyl radical oxidative species are generated following gyrase poisoning and play an important role in cell killing by gyrase inhibitors. We show that superoxide-mediated oxidation of iron–sulfur clusters promotes a breakdown of iron regulatory dynamics; in turn, iron misregulation drives the generation of highly destructive hydroxyl radicals via the Fenton reaction. Importantly, our data reveal that blockage of hydroxyl radical formation increases the survival of gyrase-poisoned cells. Together, this series of biochemical reactions appears to compose a maladaptive response, that serves to amplify the primary effect of gyrase inhibition by oxidatively damaging DNA, proteins and lipids.

          Related collections

          Most cited references83

          • Record: found
          • Abstract: found
          • Article: not found

          Gene Ontology: tool for the unification of biology

          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Mitochondria and apoptosis.

            D Green, J Reed (1998)
            A variety of key events in apoptosis focus on mitochondria, including the release of caspase activators (such as cytochrome c), changes in electron transport, loss of mitochondrial transmembrane potential, altered cellular oxidation-reduction, and participation of pro- and antiapoptotic Bcl-2 family proteins. The different signals that converge on mitochondria to trigger or inhibit these events and their downstream effects delineate several major pathways in physiological cell death.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Bacterial iron homeostasis.

              Iron is essential to virtually all organisms, but poses problems of toxicity and poor solubility. Bacteria have evolved various mechanisms to counter the problems imposed by their iron dependence, allowing them to achieve effective iron homeostasis under a range of iron regimes. Highly efficient iron acquisition systems are used to scavenge iron from the environment under iron-restricted conditions. In many cases, this involves the secretion and internalisation of extracellular ferric chelators called siderophores. Ferrous iron can also be directly imported by the G protein-like transporter, FeoB. For pathogens, host-iron complexes (transferrin, lactoferrin, haem, haemoglobin) are directly used as iron sources. Bacterial iron storage proteins (ferritin, bacterioferritin) provide intracellular iron reserves for use when external supplies are restricted, and iron detoxification proteins (Dps) are employed to protect the chromosome from iron-induced free radical damage. There is evidence that bacteria control their iron requirements in response to iron availability by down-regulating the expression of iron proteins during iron-restricted growth. And finally, the expression of the iron homeostatic machinery is subject to iron-dependent global control ensuring that iron acquisition, storage and consumption are geared to iron availability and that intracellular levels of free iron do not reach toxic levels.
                Bookmark

                Author and article information

                Journal
                Mol Syst Biol
                Molecular Systems Biology
                1744-4292
                2007
                13 March 2007
                : 3
                : 91
                Affiliations
                [1 ]Program in Molecular Biology, Cell Biology and Biochemistry, Boston University, Boston, MA, USA
                [2 ]Center for BioDynamics and Center for Advanced Biotechnology, Boston University, Boston, MA, USA
                [3 ]Department of Biomedical Engineering, Boston University, Boston, MA, USA
                [4 ]Boston University School of Medicine, Boston, MA, USA
                [5 ]Bioinformatics Program, Boston University, Boston, MA, USA
                Author notes
                [a ]Center for BioDynamics and Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA. Tel.: +617 353 0390; Fax: +617 353 5462; jcollins@ 123456bu.edu
                [*]

                These authors contributed equally to this work

                Article
                msb4100135
                10.1038/msb4100135
                1847949
                17353933
                d2e6f8db-f56e-4b05-b22a-8b870c732e7c
                Copyright © 2007, EMBO and Nature Publishing Group
                History
                : 10 November 2006
                : 26 January 2007
                Page count
                Pages: 1
                Categories
                Article

                Quantitative & Systems biology
                iron–sulfur cluster,oxidative damage,hydroxyl radicals,gyrase inhibitors,systems biology

                Comments

                Comment on this article