Quantitative high-throughput screening identifies inhibitors of anthrax-induced cell death.

Methods Development

Abstract

Here, we report the results of a quantitative high-throughput screen (qHTS) measuring the endocytosis and translocation of a beta-lactamase-fused-lethal factor and the identification of small molecules capable of obstructing the process of anthrax toxin internalization. Several small molecules protect RAW264.7 macrophages and CHO cells from anthrax lethal toxin and protected cells from an LF-Pseudomonas exotoxin fusion protein and diphtheria toxin. Further efforts demonstrated that these compounds impaired the PA heptamer pre-pore to pore conversion in cells expressing the CMG2 receptor, but not the related TEM8 receptor, indicating that these compounds likely interfere with toxin internalization.

Authors

Zhu, Ping Jun; Hobson, John P; Southall, Noel; Qiu, Cunping; Thomas, Craig; Lu, Jiamo; Inglese, James; Zheng, Wei; Leppla, Stephen H; Bugge, Thomas H; Austin, Christopher; Liu, Shihui;

Keywords

  • Animals
  • Anthrax/ drug therapy
  • Anti-Bacterial Agents/ chemistry
  • Anti-Bacterial Agents/ pharmacology
  • Antigens, Bacterial/ metabolism
  • Bacillus anthracis/ drug effects
  • Bacillus anthracis/ metabolism
  • Bacterial Proteins/ antagonists & inhibitors
  • Bacterial Proteins/ metabolism
  • Bacterial Toxins/ antagonists & inhibitors
  • Bacterial Toxins/ metabolism
  • CHO Cells
  • Cell Death/ drug effects
  • Corynebacterium diphtheriae/ metabolism
  • Cricetinae
  • Cricetulus
  • Diphtheria Toxin/ antagonists & inhibitors
  • Diphtheria Toxin/ metabolism
  • Endocytosis/ drug effects
  • Exotoxins/ antagonists & inhibitors
  • Exotoxins/ metabolism
  • Macrophages/ cytology
  • Macrophages/ drug effects
  • Mice
  • Pseudomonas/ metabolism
  • Small Molecule Libraries/ chemistry
  • Small Molecule Libraries/ pharmacology

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