- Treffer 1 von 1
Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-130097
- Background Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric \(PA_{63}\) binding/translocation component are related phenomena. ChloroquineBackground Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric \(PA_{63}\) binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the \(PA_{63}\)-channel in a dose dependent way. Methodology/Principal Findings Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the \(PA_{63}\)-channel in the µM range, when both, inhibitor and \(PA_{63}\) are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of \(PA_{63}\)-channel function also efficiently block intoxication of the cells by the combination lethal factor and \(PA_{63}\) in the same concentration range as they block the channels in vitro. Conclusions/Significance These results strongly argue in favor of a transport of lethal factor through the \(PA_{63}\)-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax.…
Autor(en): | Christoph Beitzinger, Annika Bronnhuber, Kerstin Duscha, Zsuzsanna Riedl, Markus Huber-Lang, Roland Benz, György Hajos, Holger Barth |
---|---|
URN: | urn:nbn:de:bvb:20-opus-130097 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Fakultät für Biologie / Rudolf-Virchow-Zentrum |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | PLoS ONE |
Erscheinungsjahr: | 2013 |
Band / Jahrgang: | 8 |
Heft / Ausgabe: | 6 |
Seitenangabe: | e66099 |
Originalveröffentlichung / Quelle: | PLoS ONE 8(6): e66099. doi:10.1371/journal.pone.0066099 |
DOI: | https://doi.org/10.1371/journal.pone.0066099 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | anthrax; cell membranes; chloroquine; intoxication; lipid bilayer; macrophages; membrane potential; toxins |
Datum der Freischaltung: | 05.07.2016 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung |