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Identification of novel host-targeted compounds that protect from anthrax lethal toxin-induced cell death
Louise H Slater1, Erik C Hett, Kevin Mark
1Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
Abstract:
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.
Insights
Researchers identified small molecules that inhibit Bacillus anthracis lethal toxin, protecting macrophages from cell death. These compounds offer new strategies for treating toxin-mediated diseases.
Area of Science:
- Cell Biology
- Pathogen-Host Interactions
- Toxicology
Background:
- Pathogen subversion of host cells is crucial for disease development.
- Bacillus anthracis lethal toxin (LT) is a key virulence factor that impairs host immunity and causes pathology.
- Understanding LT's mechanism is vital for developing countermeasures.
Purpose of the Study:
- To identify small molecules that inhibit LT-induced macrophage cell death.
- To characterize the mechanisms of action of identified inhibitors.
- To explore potential therapeutic strategies against toxin-mediated diseases.
Main Methods:
- Phenotypic small molecule screen for LT inhibitors.
- Secondary assays to characterize compound effects on cellular function.
- Testing compounds against Clostridium difficile toxin TcdB.
Main Results:
- Identified diverse small molecules inhibiting LT at various pathway points.
- Discovered inhibitors of endocytosis, organelle acidification, and a novel proteasome inhibitor (4MNB).
- Several compounds, including approved drugs, protected against both LT and TcdB.
Conclusions:
- Small molecules can effectively inhibit LT-induced cell death.
- Identified compounds serve as valuable tools for studying toxin biology.
- These findings suggest novel therapeutic approaches for toxin-mediated diseases.
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