Quantitative high-throughput screening identifies inhibitors of anthrax-induced cell death.
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.
Zhu
Ping Jun
PJ
NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, United States.
Hobson
John P
JP
Southall
Noel
N
Qiu
Cunping
C
Thomas
Craig J
CJ
Lu
Jiamo
J
Inglese
James
J
Zheng
Wei
W
Leppla
Stephen H
SH
Bugge
Thomas H
TH
Austin
Christopher P
CP
Liu
Shihui
S
D000818:Animals; D000881:Anthrax / Q000188:drug therapy*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000187:drug effects / Q000378:metabolism*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016466:CHO Cells; D016923:Cell Death / Q000187:drug effects; D003353:Corynebacterium diphtheriae / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004167:Diphtheria Toxin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects*; D005098:Exotoxins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D011549:Pseudomonas / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004167:Diphtheria Toxin; D005098:Exotoxins; D054852:Small Molecule Libraries; C030325:anthrax toxin