Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death.
Studying how pathogens subvert the host to cause disease has contributed to the understanding of fundamental cell biology. Bacillus anthracis, the causative agent of anthrax, produces the virulence factor lethal toxin to disarm host immunity and cause pathology. We conducted a phenotypic small molecule screen to identify inhibitors of lethal toxin-induced macrophage cell death and used an ordered series of secondary assays to characterize the hits and determine their effects on cellular function. We identified a structurally diverse set of small molecules that act at various points along the lethal toxin pathway, including inhibitors of endocytosis, natural product inhibitors of organelle acidification (e.g., the botulinum neurotoxin inhibitor, toosendanin), and a novel proteasome inhibitor, 4MNB (4-methoxy-2-[2-(5-methoxy-2-nitrosophenyl)ethyl]-1-nitrosobenzene). Many of the compounds, including three drugs approved for use in humans, also protected against the related Clostridium difficile toxin TcdB, further demonstrating their value as novel tools for perturbation and study of toxin biology and host cellular processes and highlighting potential new strategies for intervening on toxin-mediated diseases.
Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Louise H
LH
Slater
Erik C
EC
Hett
Kevin
K
Mark
Nicole M
NM
Chumbler
Deepa
D
Patel
D Borden
DB
Lacy
R John
RJ
Collier
Deborah T
DT
Hung
D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D057166:High-Throughput Screening Assays; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D014315:Triterpenes
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004365:Drugs, Chinese Herbal; C030325:anthrax toxin; C036454:toosendanin; D014315:Triterpenes