Bacterial pathogenesis involves at least two steps: 1- attachment of the bacteria to the host tissue to be infected, and 2- secretion of toxic molecules by the bacteria. Both steps are mediated by a fibrous structure displayed at the surface of the bacteria called a """"""""pilus"""""""". On one end of the pilus (facing outwards), the pilus harbours a protein called """"""""adhesin"""""""" which binds specifically to the host's surface polysaccharides. On the other end, the pilus may be attached to a secretion machinery responsible for injection of toxic substances. The pilus itself is a complex polymer of several different protein subunits. In this proposal, we propose to study the structural basis of 1- pilus biogenesis, 2- bacterial attachment to the host tissue, and 3-protein secretion. We have used the type P pili of uropathogenic Escherichia coli as a model to study pilus biogenesis and bacterial attachment, and we have used the type IV secretion system of the ulcer-causing Helicobacter pylori as a model to study the secretion of proteins by bacteria. We have obtained several crystals of pilus subunits in complex with their assembly chaperone; we have also crystallized binary complexes of adhesins with their cognate polysaccharides; and finally, we have crystallized important components of the type IV secretion machinery. Two of these structures have been or are in the process of being solved. Our proposal, by seeking to understand the structural basis of pathogenicity in bacteria responsible for important infectious diseases, will have not only an impact on the fundamental knowledge of the various systems under study, but will also help design antibiotic compounds which are effective in the fight against these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049950-02
Application #
6511589
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Hall, Robert H
Project Start
2001-06-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$385,000
Indirect Cost
Name
Washington University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
O'Brien, Valerie P; Hannan, Thomas J; Nielsen, Hailyn V et al. (2016) Drug and Vaccine Development for the Treatment and Prevention of Urinary Tract Infections. Microbiol Spectr 4:
Spaulding, Caitlin N; Hultgren, Scott J (2016) Adhesive Pili in UTI Pathogenesis and Drug Development. Pathogens 5:
O'Brien, Valerie P; Hannan, Thomas J; Schaeffer, Anthony J et al. (2015) Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. Curr Opin Infect Dis 28:97-105
Kostakioti, Maria; Hadjifrangiskou, Maria; Hultgren, Scott J (2013) Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era. Cold Spring Harb Perspect Med 3:a010306
Monack, Denise M; Hultgren, Scott J (2013) The complex interactions of bacterial pathogens and host defenses. Curr Opin Microbiol 16:1-3
Ford, Bradley; Verger, Denis; Dodson, Karen et al. (2012) The structure of the PapD-PapGII pilin complex reveals an open and flexible P5 pocket. J Bacteriol 194:6390-7
Chorell, Erik; Pinkner, Jerome S; Bengtsson, Christoffer et al. (2012) Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study. Bioorg Med Chem 20:3128-42
Hannan, Thomas J; Totsika, Makrina; Mansfield, Kylie J et al. (2012) Host-pathogen checkpoints and population bottlenecks in persistent and intracellular uropathogenic Escherichia coli bladder infection. FEMS Microbiol Rev 36:616-48
Chorell, Erik; Pinkner, Jerome S; Bengtsson, Christoffer et al. (2012) Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms. Chemistry 18:4522-32
Cusumano, Corinne K; Pinkner, Jerome S; Han, Zhenfu et al. (2011) Treatment and prevention of urinary tract infection with orally active FimH inhibitors. Sci Transl Med 3:109ra115

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