title: Evaluation of combination therapy for Burkholderia cenocepacia lung infection in different in vitro and in vivo models.
abstract: Burkholderia cenocepacia is an opportunistic pathogen responsible for life-threatening infections in cystic fibrosis patients. B. cenocepacia is extremely resistant towards antibiotics and therapy is complicated by its ability to form biofilms. We investigated the efficacy of an alternative antimicrobial strategy for B. cenocepacia lung infections using in vitro and in vivo models. A screening of the NIH Clinical Collection 1&2 was performed against B. cenocepacia biofilms formed in 96-well microtiter plates in the presence of tobramycin to identify repurposing candidates with potentiator activity. The efficacy of selected hits was evaluated in a three-dimensional (3D) organotypic human lung epithelial cell culture model. The in vivo effect was evaluated in the invertebrate Galleria mellonella and in a murine B. cenocepacia lung infection model. The screening resulted in 60 hits that potentiated the activity of tobramycin against B. cenocepacia biofilms, including four imidazoles of which econazole and miconazole were selected for further investigation. However, a potentiator effect was not observed in the 3D organotypic human lung epithelial cell culture model. Combination treatment was also not able to increase survival of infected G. mellonella. Also in mice, there was no added value for the combination treatment. Although potentiators of tobramycin with activity against biofilms of B. cenocepacia were identified in a repurposing screen, the in vitro activity could not be confirmed nor in a more sophisticated in vitro model, neither in vivo. This stresses the importance of validating hits resulting from in vitro studies in physiologically relevant model systems.
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Freija
authors.initials: F
authors.lastname: Van den Driessche
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Wilrijk, Belgium.
authors.forename: Bieke
authors.initials: B
authors.lastname: Vanhoutte
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Brackman
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Crabbé
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Petra
authors.initials: P
authors.lastname: Rigole
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Vercruysse
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Glenn
authors.initials: G
authors.lastname: Verstraete
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Wilrijk, Belgium.
authors.forename: Davie
authors.initials: D
authors.lastname: Cappoen
authors.affiliation: Laboratory of Pharmaceutical Technology, Ghent University, Ghent, Belgium.
authors.forename: Chris
authors.initials: C
authors.lastname: Vervaet
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Wilrijk, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.affiliation: Laboratory of Pharmaceutical Microbiology, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.identifier: http://orcid.org/0000-0002-6407-0601
authors.initials: T
authors.lastname: Coenye
mesh_terms: D000072283:A549 Cells; D000818:Animals; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D019121:Burkholderia Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D057508:Burkholderia cenocepacia / Q000502:physiology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination / Q000379:methods; D004464:Econazole / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008825:Miconazole / Q000494:pharmacology*; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014031:Tobramycin / Q000494:pharmacology*
chemical_list: D004464:Econazole; D008825:Miconazole; D014031:Tobramycin