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Infection and Immunity, September 2007, p. 4552-4561, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00442-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of Small Molecules That Inhibit Intracellular Toxin Transport{triangledown} ,{dagger}

Jose B. Saenz, Teresa A. Doggett, and David B. Haslam*

Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63110

Received 26 March 2007/ Returned for modification 24 April 2007/ Accepted 7 June 2007

Shiga toxin (Stx), cholera toxin (Ctx), and the plant toxin ricin are among several toxins that reach their intracellular destinations via a complex route. Following endocytosis, these toxins travel in a retrograde direction through the endosomal system to the trans-Golgi network, Golgi apparatus, and endoplasmic reticulum (ER). There the toxins are transported across the ER membrane to the cytosol, where they carry out their toxic effects. Transport via the ER from the cell surface to the cytosol is apparently unique to pathogenic toxins, raising the possibility that various stages in the transport pathway can be therapeutically targeted. We have applied a luciferase-based high-throughput screen to a chemical library of small-molecule compounds in order to identify inhibitors of Stx. We report two novel compounds that protect against Stx and ricin inhibition of protein synthesis, and we demonstrate that these compounds reversibly inhibit bacterial transport at various stages in the endocytic pathway. One compound (compound 75) inhibited transport at an early stage of Stx and Ctx transport and also provided protection against diphtheria toxin, which enters the cytosol from early endosomes. In contrast, compound 134 inhibited transport from recycling endosomes through the Golgi apparatus and protected only against toxins that access the ER. Small-molecule compounds such as these will provide insight into the mechanism of toxin transport and lead to the identification of compounds with therapeutic potential against toxins routed through the ER.

* Corresponding author. Mailing address: Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 286-2888. Fax: (314) 286-2895. E-mail: haslam{at}kids.wustl.edu

{triangledown} Published ahead of print on 18 June 2007.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: D. L. Burns

Infection and Immunity, September 2007, p. 4552-4561, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00442-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Quinones, B., Massey, S., Friedman, M., Swimley, M. S., Teter, K. (2009). Novel Cell-Based Method To Detect Shiga Toxin 2 from Escherichia coli O157:H7 and Inhibitors of Toxin Activity. Appl. Environ. Microbiol. 75: 1410-1416 [Abstract] [Full Text]  


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