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Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections

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  • Authors: Zachary T. Cusumano1, Roger D. Klein2, Scott J. Hultgren3
  • Editors: Indira T. Kudva4, Bryan H. Bellaire5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110; 2: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110; 3: Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO 63110; 4: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 5: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
  • Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
  • Received 10 July 2015 Accepted 16 September 2015 Published 18 March 2016
  • Scott J. Hultgren, hultgren@wusm.wustl.edu
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  • Abstract:

    Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

  • Citation: Cusumano Z, Klein R, Hultgren S. 2016. Innovative Solutions to Sticky Situations: Antiadhesive Strategies for Treating Bacterial Infections. Microbiol Spectrum 4(2):VMBF-0023-2015. doi:10.1128/microbiolspec.VMBF-0023-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0023-2015
2016-03-18
2017-08-20

Abstract:

Bacterial adherence to host tissue is an essential process in pathogenesis, necessary for invasion and colonization and often required for the efficient delivery of toxins and other bacterial effectors. As existing treatment options for common bacterial infections dwindle, we find ourselves rapidly approaching a tipping point in our confrontation with antibiotic-resistant strains and in desperate need of new treatment options. Bacterial strains defective in adherence are typically avirulent and unable to cause infection in animal models. The importance of this initial binding event in the pathogenic cascade highlights its potential as a novel therapeutic target. This article seeks to highlight a variety of strategies being employed to treat and prevent infection by targeting the mechanisms of bacterial adhesion. Advancements in this area include the development of novel antivirulence therapies using small molecules, vaccines, and peptides to target a variety of bacterial infections. These therapies target bacterial adhesion through a number of mechanisms, including inhibition of pathogen receptor biogenesis, competition-based strategies with receptor and adhesin analogs, and the inhibition of binding through neutralizing antibodies. While this article is not an exhaustive description of every advancement in the field, we hope it will highlight several promising examples of the therapeutic potential of antiadhesive strategies.

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FIGURE 1

Comparison of structure and assembly mechanism of common extracellular adhesive organelles. Following translocation through the SecYEG apparatus, the FimA structural subunits are bound by the FimC chaperone via the donor strand complementation reaction before delivery to the FimD usher, which catalyzes a donor strand exchange reaction that links subunits of the growing pilus. In the periplasmic space, soluble CsgA binds the CsgE chaperone, which delivers it to the CsgG pore for secretion to the outer membrane. From there, its folding and polymerization is nucleated by CsgB, which is anchored to the outer membrane by the CsgF assembly factor. Ebp pilus subunits integrate themselves into the membrane, where the dedicated pilus assembly sortase, SrtC, cleaves the sorting sequence and facilitates the nucleophilic attack by a new incoming subunit. The fully assembled pilus is then integrated into the membrane by the housekeeping sortase, SrtA.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 2

Inhibitors of the donor strand exchange reaction between pilus subunits are able to abrogate pilus biogenesis. Crystal structure of the FimG adaptor’s donor strand exchange reaction with the pilin domain of the FimH adhesin (PDB ID code 3JWN). FimG donates its hydrophobic N-terminal beta strand to FimH, which is shown residing in the P5 pocket. Schematic of the donor strand complementation and donor strand exchange pathways. The donor strand complementation reaction between the chaperone G1 strand and the bound pilin results in a noncanonical parallel fashion (left panel), while the zip-in, zip-out process underlying the DSE reactions results in the formation of an antiparallel, low-energy interaction (adapted from reference 240 ). Chemical structure of compound 3, first identified from an docking assay before further refinement in DSE assays.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 3

Small molecules known as “pilicides” disrupt pilus biogenesis. Structures of two potent curlicides. Curlicide 1 disrupts type 1, P, and S pili. Curlicide 2 binds to the P pilus chaperone PapD, inhibiting its interaction with the PapC usher. Electron micrographs demonstrating a loss of P pili on uropathogenic cells exposed to increasing concentrations of curlicide 2 (adapted from reference 150 , with permission; copyright [2006] National Academy of Sciences, USA). Crystal structure of the two-domain adhesin FimH complexed with pilicide (PDB ID code 2J7L).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 4

Curlicides inhibit biofilm formation. Structure of the curlicide 4 compound. Curlicide compounds are based on 2-pyridine scaffold functionalized with a variety of substituents. Inhibition of extracellular curli formation in the presence of increasing concentrations of curlicide 4 (adapted from reference 126 ).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 5

Potent inhibitors of sortase A function. X-ray crystal structure of sortase A from (PDB ID code 2KID) with docking of compound 5, which binds directly to the active site of the enzyme (adapted from reference 170 , with permission). Structure of the sortase inhibitor compound 5, which inhibits sortase A from with an IC of 9.3 μM and with an IC of 0.82 μM.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 6

Mannosides are potent inhibitors of FimH binding. Crystal structure of FimH complexed with mannoside 8, which binds to FimH with an affinity over 1 million times higher than its natural substrate, -mannose (PDB ID code 3MCY). Structure of a variety of mannosides, each rationally designed to increase affinity for FimH by interacting with the hydrophobic ridge outside of the mannose-binding pocket. Although heptyl α--mannoside 6 successfully bound FimH with a 600 times increased affinity when compared to -mannoside, the biphenyl substituents ultimately proved to be the most effective compounds (7, 8, and 9).

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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FIGURE 7

Inhibitors of soluble lectins LecA and LecB. Structural depiction of the tetravalent calixarene scaffold, which can be functionalized with galactose and fucose moieties using triethylene glycol linkers to form compounds 11 and 10, respectively. Monovalent inhibitor of LecA 12 binds with a K of 4.2 μM. Monovalent inhibitor of LecB 13 activity binds with a K of 3.3 μM.

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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Tables

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TABLE 1

Antiadhesive small molecules

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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TABLE 2

Antiadhesive strategies targeting the Gram-positive sortase

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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TABLE 3

Antiadhesive strategies utilizing receptor and adhesin analogs

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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TABLE 4

Antiadhesive strategies utilizing antiadhesin vaccines or antibodies

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015
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TABLE 5

Antiadhesive strategies utilizing dietary supplements

Source: microbiolspec March 2016 vol. 4 no. 2 doi:10.1128/microbiolspec.VMBF-0023-2015

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