Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.

TitleRationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.
Publication TypeJournal Article
Year of Publication2006
AuthorsPinkner, J. S., H. Remaut, F. Buelens, E. Miller, V. Aberg, N. Pemberton, M. Hedenström, A. Larsson, P. Seed, G. Waksman, S. J. Hultgren, and F. Almqvist
JournalProc Natl Acad Sci U S A
Volume103
Issue47
Pagination17897-902
Date Published2006 Nov 21
Type of Articlesmm
ISSN0027-8424
KeywordsAnti-Bacterial Agents, Bacterial Adhesion, Bicyclo Compounds, Biofilms, Crystallography, X-Ray, Drug Design, Escherichia coli, Escherichia coli Proteins, Fimbriae Proteins, Fimbriae, Bacterial, Humans, Models, Molecular, Molecular Chaperones, Molecular Structure, Periplasmic Proteins, Point Mutation, Protein Conformation, Pyridones, Urinary Bladder, Urinary Tract Infections, Virulence Factors
Abstract

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 approximately 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.

DOI10.1073/pnas.0606795103
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID17098869
PubMed Central IDPMC1693844
Grant ListK12-HD00850 / HD / NICHD NIH HHS / United States
R01 AI48689-05 / AI / NIAID NIH HHS / United States
R37 AI029549 / AI / NIAID NIH HHS / United States