Amiodarone and bepridil inhibit anthrax toxin entry into host cells.
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.
Sanchez
Ana M
AM
Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Thomas
Diane
D
Gillespie
Eugene J
EJ
Damoiseaux
Robert
R
Rogers
Joseph
J
Saxe
Jonathan P
JP
Huang
Jing
J
Manchester
Marianne
M
Bradley
Kenneth A
KA
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
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; D015764:Bepridil; D002738:Chloroquine; D000242:Cyclic AMP; D000638:Amiodarone