Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Beitzinger, Christoph and Bronnhuber, Anika and Duscha, Kerstin and Riedl, Zsuzsanna and Hajós, György (2013) Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin. PLOS ONE, 8 (6). ISSN 1932-6203

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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 PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 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 PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 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 PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al.

Item Type: Article
Uncontrolled Keywords: target cell; nonhuman; NOISE; Membrane transport; MACROPHAGE; in vivo study; in vitro study; endosome; drug mechanism; controlled study; channel gating; cell protection; Bacillus anthracis; ARTICLE; animal cell; unindexed drug; unclassified drug; quinolone derivative; pyridinium derivative; protective antigen; heterocyclic compound; ha 766; ha 728; ha 708; ha 486; ha 47; ha 42; ha 1885; ha 1882; ha 1568; ha 1504; ha 1495; ha 1383; ha 1371; ha 1221; ha 1212; ha 1196; ha 112; chloroquine; bacterial toxin; bacterial protein; bacterial enzyme; azolopyridinium salt; anthrax toxin; Anthrax lethal factor; 4 aminoquinolone; 1 (4 hydroxyphenyl) 2 (4 nitrophenyl)imidazo[1,2 a]pyridinium tetrafluoroborate; 1 (4 chlorophenyl) 2 (4 bromophenyl)imidazo[1,2 a]pyridinium etrafluoroborate; 1 (3 nitrophenyl) 2 (4 bromophenyl)imidazo[1,2a]pyridinium bromide
Subjects: Q Science / természettudomány > QD Chemistry / kémia
Depositing User: MTMT SWORD
Date Deposited: 04 Oct 2013 09:21
Last Modified: 07 Oct 2013 06:56

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