Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria
| Autor: | Gabriel Waksman, Han Remaut, Andreas Larsson, Nils Pemberton, Veronica Åberg, Jerome S. Pinkner, Eric L. Miller, Mattias Hedenström, Fredrik Almqvist, Floris Buelens, Scott J. Hultgren, Patrick C. Seed |
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| Přispěvatelé: | Department of Bio-engineering Sciences, Structural Biology Brussels |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Pyridones Virulence Factors Protein Conformation Bridged Bicyclo Compounds/chemical synthesis Fimbria Urinary Bladder Virulence Anti-Bacterial Agents/chemical synthesis Molecular Chaperones/chemistry Fimbriae Bacterial/drug effects molecular structure Pyridones/chemical synthesis medicine.disease_cause Crystallography X-Ray Periplasmic Proteins/chemistry Pilus Bacterial Adhesion Fimbriae Proteins Bridged Bicyclo Compounds Urinary Bladder/cytology medicine Escherichia coli Fimbriae Proteins/genetics Humans Point Mutation Multidisciplinary Escherichia coli/drug effects biology Escherichia coli Proteins Bacterial Adhesion/drug effects Biological Sciences Virulence Factors/antagonists & inhibitors Anti-Bacterial Agents Biochemistry Chaperone (protein) Fimbriae Bacterial Drug Design Escherichia coli Proteins/chemistry Urinary Tract Infections biology.protein Periplasmic Proteins biofilms Urinary Tract Infections/drug therapy Bacterial outer membrane Biogenesis Molecular Chaperones |
| Popis: | A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone–usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli . Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by ≈90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone–subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors. |
| Databáze: | OpenAIRE |
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