title: Amiodarone and bepridil inhibit anthrax toxin entry into host cells.
abstract: Anthrax lethal toxin is one of the fundamental components believed to be responsible for the virulence of Bacillus anthracis. In order to find novel compounds with anti-lethal toxin properties, we used a cell-based assay to screen a collection of approximately 500 small molecules. Nineteen compounds that blocked lethal toxin-mediated killing of RAW 264.7 macrophages were identified, and we report here on the characterization of the two most potent antitoxic compounds, amiodarone and bepridil. These drugs are used to treat cardiac arrhythmia or angina in humans at doses similar to those that provide protection against lethal toxin in vitro. Our results support a model whereby the antitoxic properties of both drugs result from their ability to block endosomal acidification, thereby blocking toxin entry. Amiodarone was tested in vivo and found to significantly increase survival of lethal toxin-challenged Fischer rats.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sanchez
authors.forename: Diane
authors.initials: D
authors.lastname: Thomas
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Gillespie
authors.forename: Robert
authors.initials: R
authors.lastname: Damoiseaux
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Saxe
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Marianne
authors.initials: M
authors.lastname: Manchester
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
mesh_terms: D000638:Amiodarone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000881:Anthrax / Q000517:prevention & control*; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D015764:Bepridil / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016466:CHO Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000382:microbiology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D015764:Bepridil; D002738:Chloroquine; D000242:Cyclic AMP; D000638:Amiodarone