Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses

Eugene J. Gillespie, Chi Lee C. Ho, Kavitha Balaji, Daniel L. Clemens, Gang Deng, Yao E. Wang, Heidi J. Elsaesser, Batcha Tamilselvam, Amandeep Gargi, Shandee D. Dixon, Bryan France, Brian T. Chamberlain, Steven R. Blanke, Genhong Cheng, Juan Carlos De La Torre, David G. Brooks, Michael E. Jung, John Colicelli, Robert Damoiseaux, Kenneth A. Bradley

Research output: Contribution to journalArticle

Abstract

Pathogenic microorganisms and toxins have evolved a variety of mechanisms to gain access to the host-cell cytosol and thereby exert virulent effects upon the host. One common mechanism of cellular entry requires trafficking to an acidified endosome, which promotes translocation across the host membrane. To identify small-molecule inhibitors that block this process, a library of 30,000 small molecules was screened for inhibitors of anthrax lethal toxin. Here we report that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semi-carbazone, themost active compound identified in the screen, inhibits intoxication by lethal toxin and blocks the entry ofmultiple other acid-dependent bacterial toxins and viruses into mammalian cells. This compound,whichwe named EGA, also delays lysosomal targeting and degradation of the EGF receptor, indicating that it targets host-membrane trafficking. In contrast, EGA does not block endosomal recycling of transferrin, retrograde traf fi cking of ricin, phagolysosomal trafficking, or phagosome permeabilization by Franciscella tularensis. Furthermore, EGA does not neutralize acidic organelles, demonstrating that its mechanism of action is distinct from pH-raising agents such as ammonium chloride and bafilomycin A1. EGA is a powerful tool for the study of membrane trafficking and represents a class of host-targeted compounds for therapeutic development to treat infectious disease.

Original languageEnglish (US)
Pages (from-to)E4904-E4912
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number50
DOIs
StatePublished - Dec 10 2013

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    Gillespie, E. J., Ho, C. L. C., Balaji, K., Clemens, D. L., Deng, G., Wang, Y. E., Elsaesser, H. J., Tamilselvam, B., Gargi, A., Dixon, S. D., France, B., Chamberlain, B. T., Blanke, S. R., Cheng, G., De La Torre, J. C., Brooks, D. G., Jung, M. E., Colicelli, J., Damoiseaux, R., & Bradley, K. A. (2013). Selective inhibitor of endosomal trafficking pathways exploited by multiple toxins and viruses. Proceedings of the National Academy of Sciences of the United States of America, 110(50), E4904-E4912. https://doi.org/10.1073/pnas.1302334110