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Designer probiotics for prevention of enteric infections

Key Points

  • For several important infectious diseases, pathogenesis depends on the capacity of the invading microorganism, or toxins that they secrete, to bind to specific oligosaccharide structures on the surface of host cells. This has led to the development of novel anti-infective strategies based on interference with receptor binding.

  • Receptor–ligand interactions are often complex. Shiga toxin and cholera toxin, for example, interact with multiple host receptors through pentameric binding subunits. As a consequence, free oligosaccharides are often not particularly effective competitive blocking agents. Studies using chemically synthesised glycoconjugates have shown that strong binding to these toxins can be achieved using multivalent ligands. The spatial configurations of the oligosaccharide moieties have been engineered to optimize docking with each receptor-binding site on the toxin B pentamer. These compounds have potential as either injectable or oral therapeutic agents.

  • An alternative approach is to express mimics of oligosaccharide receptors on the surface of harmless bacteria capable of survival within the gastrointestinal tract. Oral administration of such designer probiotics would be predicted to bind and neutralize toxins in the gut lumen, thereby preventing disease.

  • In the prototypic example, a strain of Escherichia coli was engineered to express a chimeric lipopolysaccharide, the terminal components of which mimicked the Shiga-toxin receptor. This construct bound Shiga toxin with high avidity in vitro and was highly protective against Shiga toxigenic E. coli infection in vivo. Probiotics that can bind cholera toxin and E. coli labile enterotoxin have also been constructed. Protective efficacy in animal models indicates their potential for prevention of travellers' diarrhoea and cholera.

  • Potential barriers to the clinical use of recombinant probiotics include the regulatory issues associated with release of genetically modified microorganisms. Further experimentation is also required to ensure that these bacteria do not elicit autoimmune responses after oral administration. Killed receptor-mimic bacteria can also prevent disease in animal models, and so it would be prudent to commence any human trials using such preparations.

Abstract

Many microbial pathogens, including those responsible for major enteric infections, exploit oligosaccharides that are displayed on the surface of host cells as receptors for toxins and adhesins. Blocking crucial ligand–receptor interactions is therefore a promising therapeutic strategy. One approach is to express molecular mimics of host receptors on the surface of harmless recombinant bacteria that can survive in the gut. These 'designer probiotics' bind bacterial toxins in the gut lumen with very high avidity, thereby preventing disease. This article discusses recent progress with this strategy.

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Figure 1: Schematic depiction of the receptor-mimic probiotic strategy.
Figure 2: Lipopolysaccharide (LPS) structure of the globotriaosyl ceramide (Gb3) mimic probiotic.
Figure 3: Specificity of binding of Shiga toxin (Stx) and cholera toxin (Ctx) to receptor-mimic probiotics.

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Acknowledgements

Research in the authors' laboratories was supported by the National Health and Medical Research Council and the Australian Research Council. We are also grateful to U. Talbot and L. van den Bosch for assistance with fluorescence microscopy.

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Correspondence to James C. Paton.

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The University of Adelaide, through its commercial arm Adelaide Research and Innovation Pty Ltd, has filed patents relating to the work described in this article. As the named inventors, the authors might benefit financially if this were to be commercialized.

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DATABASES

Entrez Genome Project

Campylobacter jejuni NCTC11168

Clostridium difficile

E. coli K12

Haemophilus influenzae

Helicobacter pylori

Neisseria gonorrhoeae

Neisseria meningitidis

O157:H7 STEC

Schistosoma mansoni

Shigella dysenteriae

Vibrio cholerae

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Paton, A., Morona, R. & Paton, J. Designer probiotics for prevention of enteric infections. Nat Rev Microbiol 4, 193–200 (2006). https://doi.org/10.1038/nrmicro1349

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