title: Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria.
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.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Han
authors.initials: H
authors.lastname: Remaut
authors.forename: Floris
authors.initials: F
authors.lastname: Buelens
authors.forename: Eric
authors.initials: E
authors.lastname: Miller
authors.forename: Veronica
authors.initials: V
authors.lastname: Aberg
authors.forename: Nils
authors.initials: N
authors.lastname: Pemberton
authors.forename: Mattias
authors.initials: M
authors.lastname: Hedenström
authors.forename: Andreas
authors.initials: A
authors.lastname: Larsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Seed
authors.forename: Gabriel
authors.initials: G
authors.lastname: Waksman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001422:Bacterial Adhesion / Q000187:drug effects; D018441:Biofilms; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D036781:Fimbriae Proteins / Q000235:genetics / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D033903:Periplasmic Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011487:Protein Conformation; D011728:Pyridones / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001743:Urinary Bladder / Q000166:cytology / Q000382:microbiology; D014552:Urinary Tract Infections / Q000188:drug therapy / Q000382:microbiology; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001643:Bridged Bicyclo Compounds; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; C084330:PapD protein, E coli; D033903:Periplasmic Proteins; D011728:Pyridones; D037521:Virulence Factors; D036781:Fimbriae Proteins