title: Inhibitors of bacterial virulence identified in a surrogate host model.
abstract: Antibiotic resistance continues to reduce the number of available antibiotics, increasing the need for novel antibacterial drugs. Since the seminal work of Sir Alexander Fleming, antibiotic identification has been based exclusively on the inhibition of bacterial growth in vitro. Recently, inhibitors of bacterial virulence which interfere with bacterial pathogenesis mechanisms have been proposed as an alternative to antibiotics, and a few were discovered using assays targeting specific virulence mechanisms. Here we designed a simple surrogate host model for the measurement of virulence and systematic discovery of anti-virulence molecules, based on the interaction of Tetrahymena pyriformis and Klebsiella pneumoniae cells. We screened a library of small molecules and identified several inhibitors of virulence. In a mouse pneumonia model we confirmed that an anti-virulence molecule displayed antibacterial activity against Klebsiella pneumoniae and Pseudomonas aeruginosa, by reducing dramatically the bacterial load in the lungs. This molecule did not inhibit bacterial growth in vitro but prevented biosynthesis of the Klebsiella capsule and lipopolysaccharides, a key requirement for virulence. Our results demonstrate that anti-virulence molecules represent an alternative to antibiotics and those can be discovered using non-animal host models.
authors.affiliation: Athelas SA, Chemin des Aulx 18, CH-1228 Plan-les-Ouates, Switzerland. mb.benghezal@bluemail.ch
authors.forename: Mohammed
authors.initials: M
authors.lastname: Benghezal
authors.forename: Eric
authors.initials: E
authors.lastname: Adam
authors.forename: Aurore
authors.initials: A
authors.lastname: Lucas
authors.forename: Christine
authors.initials: C
authors.lastname: Burn
authors.forename: Michael G
authors.initials: MG
authors.lastname: Orchard
authors.forename: Christine
authors.initials: C
authors.lastname: Deuschel
authors.forename: Emilio
authors.initials: E
authors.lastname: Valentino
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Braillard
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Paccaud
authors.forename: Pierre
authors.initials: P
authors.lastname: Cosson
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D002439:Cefotaxime / Q000494:pharmacology; D015296:Ceftizoxime / Q000031:analogs & derivatives; D003520:Cyclophosphamide / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D007710:Klebsiella Infections / Q000150:complications / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009154:Mutation; D009503:Neutropenia / Q000188:drug therapy / Q000209:etiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D013769:Tetrahymena pyriformis / Q000187:drug effects / Q000254:growth & development; D013997:Time Factors; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects; D000097623:Cefpodoxime
chemical_list: D000900:Anti-Bacterial Agents; D002439:Cefotaxime; D015296:Ceftizoxime; D003520:Cyclophosphamide; D014227:Triazines; D000097623:Cefpodoxime